TW434261B - Motilin-like polypeptides with gastrointestinal motor stimulating activity - Google Patents

Abstract

This invention pertains to polypeptides having gastrointestinal motor stimulating activity represented by the formula: wherein A is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; B is L-proline or L-alanine; D is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; E is the L-stereoisomer of an aromatic, lipophilic aliphatic, or alicyclic amino acid; F is the L-stereoisomer of an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine, L-glutamic acid, or L-alanine; J is a direct bond or is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu, Z-Leu-Gln-Glu-Lys, Z-Leu-Gln-Glu-Lys-Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys, and Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly, wherein Z is selected from the group consisting of arginine, D-arginine, D-homoarginine, D-lysine, D-ornithine, D-2,4-diaminobutyric acid, D-glutamine, D-asparagine, and D-alanine; R1 is lower-alkyl or allyl; R2 is selected from the group consisting of hydrogen, lower-alkyl, propargyl, and allyl; R3 is selected from the group consisting of hydrogen, lower-alkyl, and allyl; R4 is selected from the group consisting of lower-alkyl, cycloalkyl, substituted and unsubstituted aryl, and heteroaryl, wherein the aryl substituents are selected from the group consisting of halogen, hydroxy, and lower-alkoxy; R5 is selected from the group consisting of -CH2CONH2, aminoalkyl groups, and guanidinoalkyl groups; R6 is -COOH or -CONH2; and m is 0 or 1, with the proviso that (a) when m is 0, R2 and R3 are hydrogen, and J is a direct bond, the -NH-*CH(CH2R5)R6 group has the D-configuration; (b) R5 is -CH2CONH2 only when J is Z-Leu or Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly; (c) when m=0, R2 and R3 are hydrogen, and J is Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu, Z-Leu-Gln-Glu-Lys, Z-Leu-Gln-Glu-Lys-Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys, and Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly, Z has the D configuration; and (d) the polypeptide is other than motilin.

Description

4 3 426 1 '' A7 _ B7 V. Description of the invention (1) The present invention relates to a novel polypeptide having potent stimulating activity and metabolic stability of the intestine of menthol, which can be used to treat the basic diarrhea with weakened characteristics. Symptoms of exercise activity levels, such as diabetic gastroparesis, numbness and intestinal obstruction after surgery. 'Lambda Bfi Sauru Motilin is a linear, gastrointestinal peptide hormone that stimulates the stomach, duodenum, and colon. Although its effects have not been fully understood so far, phytokines play a role in enhancing gastric movement and stimulating M protease output and may be important in regulating intercellular electromyography ^ syndrome clusters. At present, we have not purified human motilin. However, its immunological properties are strongly similar to porcine motilin. The porcine agglutinin contains 22 amino acid residues and can be expressed by the following formula; it represents: H'HM phase-, le-.Th ", · porium.slu.Leu, cl_et.c (wu… The element has a hydrophobic region from positions 1 to 5, a hydrophilic region M from positions 11 to 22, and a ligation region from positions 6 to 10. Zordin also has residues 9-20 from the primary sequence. Si Chengzhi's α-helical secondary structure [Khan et al., 29,5743-5751 '(1,9.90)].. Ii Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs {Please read the notes on the back before filling in (This page) Administering M-kinin to healthy subjects accelerates intestinal transit time and enhances gastric discharge. In vitro, motilin stimulates contraction and isolation of gastrointestinal smooth muscle cells from human and rabbit duodenal smooth muscle strips. In addition, motilin and some of its derivatives will compete with radiolabeled gastrin in the binding position of the human and rabbit stomach knots, suggesting that the stimulation of specific receptors in the intestine is an exaggerated physiological effect The report points out that the input of actin does indeed cause diarrhea in the stomach -4-This paper size applies Chinese National Standard (CNS) A4 regulations (210X297 mm) 4342 Α7 Β7

V. Description of the invention (2) Emptying solids and liquids in patients with paresis [pee ters et al., Gastroenterology 100, A480 (1991)]. In addition, motilin M has currently been used to treat patients with paralytic intestinal obstruction caused by gastrointestinal cancer [Meyer et al., Med. Klin. 86, 515-517 (1991)]. The main problem is that it has a relatively short half-life of only 4.5 minutes in the human body [Christofides et al. | Gut Science 76, 903-907 (1979)]. Because of its short half-life, the hormone must be administered by sequential input to induce therapeutic effects. Motilin-terminal amino acid sequences and certain residues in the middle are necessary for contraction [Macielag et al., Peptides 13, 565-569 (1992); Peeters et al., Peptide chain 13, 1103-1107 (1992) Peitras et al., Biochem. Biophys. Re. Commun. 183, 36_40 (1992)]. It is reported that it contains a shorter C-terminus, contains 3-5 basic amino acids, and is bonded by a position, a form of 12. The actin-like polypeptides with different amino acid substitutions at positions 1-11 are low Less or equivalent to motilin activity. However, no report shows that any of these peptides have enhanced metabolic stability. [Japanese Patent No. 2-3 1 1, 495]. Based on this, there is a strong, qualitative activity of the intestinal motility stimulating activity and enhanced metabolism. The t-like kinectin polypeptide is very useful for the treatment of weakened intestinal motility activity. J — l · -------- 「装 —I / ί 'Λ (Please read the notes on the back before filling out this page)' 1Τ • Λν The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed this invention about Μ Polypeptide with gastrointestinal motility activation expressed by the following formula: -5. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 434261 A7 B7 V. Description of the invention ((Hi) ThrK " H " Leu -I-J_NH_ CKU ^ (1) r3 CH2R4 ch2r5 Includes optically active isomers and pharmaceutically acceptable acid addition salts thereof, where: A is the stereogenicity of lipophilic waxy or aliphatic amino acids Isomers, B is proline or L-alanine, D is the L-stereoisomer of lipophilic aliphatic or cycloaliphatic amino acid, E is aromatic, lipophilic aliphatic or cycloaliphatic L-stereoisomers of amino acids, F is L-stereoisomers of aromatic or heteroaromatic amino acids, G is glycine or D-alanine, Η is L-glutamic acid or L -Glutamine, I is L-glutamine, L-glutamic acid, or L-alanine, J is a direct coupling between I and -NH-group, or 傺 is selected from Z, Z-Leu, Z * Leu-Glnt Z-Leu-Gln-Glu, Z-Leu-Glii-G lu -Lys, Z-Leu-Gln-Glu-Lys-G lu, Z-Leu-Gln-Glu-Lys-Glu ^ Arg, _ 〆 · Z-Leu ^ Gln-G Iu-Lys-G lu-Arg ^ Asn , Printed by Z-Leu-G In-G lu-Lys-G 1 u · ~ A rg-Asn-Lys, and Z-Leu-Gln-Glu-Lys-Glu-AnAsn -Lys-Gly, where Z pseudo is selected from the group consisting of arginine, D-arginine, D-spermine, D-neutral, D-guanine, D-2, 4-diaminobutyric acid , D-glutamine, D-asparagine, and D-propylamine

This paper size is applicable to China National Standards (CNS) A4 (210X297 mm) 1 {Please read the notes on the back and fill in this page} 4342S1 Card Consumer Standards Bureau of the Ministry of Economic Affairs, Consumer Consumption Du printed A7 B7 5 Description of the invention (4) Acid,

R1 is a lower alkyl group or a propenyl group,

Ra is selected from hydrogen, lower alkyl, propargyl and propenyl, and R 3 is selected from hydrogen, lower alkyl, propenyl,

Rt is selected from the group consisting of lower alkyl, cycloalkyl, substituted and unsubstituted aryl, and conical aryl, wherein the aryl may be one or more selected from hydrogen, hydroxyl, and lower alkoxy Substituted by a substituent is selected from the group consisting of -CHzCONH2, an aminoalkyl group containing 3 carbon atoms and a guanidylalkyl group containing 2 or 3 carbon atoms,

Re is -COOH or -coHH2, and m is 0 or 1, the * symbol represents an asymmetric carbon that can be in the d or L configuration and each lower alkyl group contains from 1 to 4 carbon atoms. The limiting conditions are: (a) when π is 0 · [? 2 and 1 {3 are hydrogen and J is directly bonded, -NHH (C 丨 UR &) Re group is D-configuration ~ (b) R5 is- CH2C〇hhz, but this only happens when J is Z ^ Leu or Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Ly.s-Gly, (c) when m = 〇, and j? 3 For Qi 'and J is Z, Z -Leu, Z-Leu-Gln, Z-Leu-Gln-Glu, Z-Leu-Crdn-Glu-Lys, Z-Leu-GIn-Glu-Lys ^ Glu, Z- Leu-Gln-Glu-Lys-Glu-Arg, _ Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-A rg-Asn-Lys, ^ Z -Leu-Gln_Glu-Lys-Glu-Arg-Asn-Lys-Gly, Z is in the D configuration, and (d) the polypeptide chain is not motilin. -7-The paper Λ degree applies to Chinese National Standard (CNS) A4 specification (21 OX297 mm) l · -----.—— r. Equipment—— / ____ .. (Please read the precautions on the back again Filling this page]

-I Order 3420 A7 B7 V. Description of the invention (The neokinin of the present invention is more effective in gastrointestinal anterior movement. The homogeneous solution is shown in position 13 with white position 1 2 as D-fine and position 1 as alkane stability. _ Therefore, the basic gastrointestinal arterial paralysis and intestinal obstruction and hand The present invention relates to a method for treating breastfeeding diseases, especially diseases. (1) The representative inventions are detailed in detail. Effect. The novel prok'inetic agent because of its enhanced biodegradation stability. The amino acid is better than the methionine M. The amino acid is not the L-arginine M The better-acting phenylalanine residue M is increased, and the polypeptides of the present invention can be used to treat symptoms of its level of activity, such as intestinal embolism after diabetic surgery. A powerful gastrointestinal motility activator is new to humans Reduced basic gastrointestinal transport The method includes administering peptide K to breastfeeding parents to reduce the symptoms: 'Affinity is also a bio-related device that resembles gastrointestinal stability and stubbornness, and is characterized by being mildly sick and resembling the body's official sister. Leptin-polypeptidity Glutathione peptides and effective levels of therapeutic activity Μ (Please read the precautions on the back before filling in this tile)

(Rl) mN Stomach 1 2 3 4 5 6 7 8 9 .10 11 12-,, CHCO-ABDE-Thr-FGH-Leu-IJ-NH- * CttRg (1) R3 ch2k4 ch2r5 Central Standards Bureau, Ministry of Economic Affairs Consumer cooperative printing includes optically active isomers and their acid-acceptable addition salts. In formula (I), m is an integer of 0-1, and the% symbol represents an asymmetric carbon that can be in the configuration of D or L and each low-carbon alkyl group includes%. From 1 to 4 carbon atoms. Its restrictions (A) when m is 0-, 1 {2 and 1? 3 are hydrogen and J is directly bonded, -NH-eClUCIURsUes base has a D-configuration, (b) (U is -CH2C0NH2 »but this paper scale Applicable Chinese National Standard (CNS) A4 grid (210X297 mm) 434261 ^ A 7 ___B7_ V. Description of the invention (6) This only occurs when J is Z-Uu or Z-L eu, G 1 η-G 1 u- L ys-G 1 u ”A rg 'A s η-L ys — G 1 y, (c) when ϊπ = 〇' Rh and (Ϊ3 is gas, and J is Z, Z-Leu, Z-Leu * ~ Gln. Z-Leu-Qln-Giu, Z-Leu-Gln-Glu-Lys, ZL ^ U'-Gln-GIu-Lys-Glu, Z-Leu-GIn-Glu-Lys-Glu-Arg, Z- Leu-Gln-G lu-Lys-G lu'Arg_Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys, and Z-Leu-GIn-Glu-Lys-Glu-Arg-Asn-Lys -Gly, Z has a D configuration, and (d)-the polypeptide is not a kinetin. The A to J groups and the ^ to [^ groups are defined as follows. The novel compounds of the present invention as defined by formula U) may be of length 12-22 amino acid peptides, and M length is 12, 14, 16 18, 20 or 22 amino acids are preferred. The stereochemistry of the amino acids constituting the novel polypeptide is κ > * an essential feature of the present invention. Unless otherwise specified ~ the absolute stereochemistry of each amino acid is L, But position 1 (amino terminal amino acid r (Rd m (R2) (R3) N- * CH (CiUR4) C0-) can be L or D, position 8 (G group) can be glycine or D -Alanine, position 12 may be L or D and 〇 terminal amino acid position -1 ^-* {: 丨 丨 ((: [^ 1? 5) 1 ^ may be / or 0 except. The following patents are used throughout The abbreviations of the application are defined as follows: _

Phe-Phenylalanine Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

Tyr-tyrosine__ NU-n-leucine / L eu-leucine, C ha-y3 -cyclohexyl alanine-9- This paper is sized for China National Standard (CNS) A4 (& X 297 (Mm) 434211 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (7):

Val-valine lie-isoleucine Gly-glycine AU-alanine ^ CJU ^ glutamate G 1-10 ~ glutamine Ars-arginine h-Arg-homospermine 0 r η -Bird limb acid Dab-2, 4-diaminobutyric acid Lys-Lysine

Asn-asparagine ''

Me-methyl

Boc-third-butoxycarbonyl-,

Cbz-benzyloxycarbonyl

Dhbt- 3, 4-dihydro-4-oxobenzotriazo-3-yl Fmoc-Methoxymethoxycarbonyl

Mbh-4, 4 ′ -dimethoxydibenzyl,, it

Mtr-4-methoxy_2,3,6-trimethylbenzenesulfonyl 1 Pfp-pentafluorophenyl

Trt-trityl 'B0P-benzotripyroxy-tridimethylamine / ylphosphine hexafluorophosphate DCC-N, N'-dicyclohexylcarbodiamidine DCM-dichloro Methane " 10 * " (Please read the precautions on the back and fill in this page)

This paper size applies to Chinese National Standard (CNS) A4 (210X297), 434261 A7 B7 V. Description of the invention (S). · · DIC-diisopropylcarbodiimide DIEA-diisopropylethylamine EDCC -N-Diethylaminopropylcyclohexylcarbodiimide ^^ 1'1] -2- (1 (1-benzotripyrrole-1-yl) -1,1,3,3-tetra Methylaldehyde carboxyl fluorofluoride HEPES- (N- [2-hydroxyethyl] pyridine-N '-[2-ethanesulfonic acid]) HMPA-hydroxymethylbenzyloxyethoxy HOBt- 1-Hydroxybenzotripyrrole MBHA-4 Dimethyldimethylbenzylamino PAH -Hydroxymethylphenylacetamidomethyl

PyBrOP-bromo-tris-pyrrolidinyl-o-hexafluorophosphate DMF-N, N-dimethylformamidine 'N Μ M-N-methylmorpholine methylpyrrolidine IX, TCA-Tri Ammonium acetic acid 'TEA-triethylamine TFA-trifluoroacetic acid TPMSA-trifluoromethanesulfonic acid, j) 1st position, amine / amino-terminated acid, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: (Please read β Please fill in the details on the back page) (Ri) ra (Rz) CR siN- ^ CH (CH2R4) C0-In (R :) m (R2) (R3) N-XH (CH2r /) CO-polypeptide The amino acid at position 1 of the base can be in the L or D configuration. 1 ^ is a lower alkyl or propenyl, 1 ^ may be selected from the group consisting of hydrogen, lower alkyl, propargyl and propenyl, and R3 may be only _1 paper size, using Chinese national standards (CNS) A4 specification (210X297 mm) 4342S1 Printed by A7 _B7_____ of the Consumer Cooperative Bureau of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (9) 乂 *. · 'Can be composed of hydrogen, lower alkyl and propylene Selected in the base. As used herein &quot; lower alkyl, &quot; this term means a radical containing straight and branched chain hydrocarbons of 4 carbon atoms. Examples of suitable lower alkyl groups for Ri, R2, and R3 are methyl, ethyl, propyl <isopropyl, butyl, isobutyl, and secondary-butyl> preferably methyl . The integer m is 0 or 1, and M0 is preferred. When m is 0, the amine residue may be primary amine, wherein 1 to 2 and 113 are hydrogen. The amine residue may also be a secondary, tertiary, or tetraammonium ammonium substituted with one, two, or three lower carbon alkyl groups (k methyl or ethyl is preferred) having one to four carbon atoms. Salt U is 1). Amine residues may also be provided by monopropargyl substitutions, such as N-propargyl, methyl-N-propyl, N, N-dimethyl-N-propargyl substituted amine residues, or逹 Three acrylic groups. Preferably, the amino terminal amino acid is N-substituted, and the preferred substituent is 1-3 methyl groups. 1 ~ 4 is selected from lower alkyl, cycloalkyl ~ with and without substituted aryl K and heteroaryl * where the aryl group may contain one or more of Selected substituents for each alkoxy group. Preferred unsubstituted aryl groups are phenyl, p-aeroyl, p-aerophenyl, p-bromobenzyl, p-iodophenyl, p-hydroxyphenyl, p-methoxy, Phenyl, tetranaphthyl, 2-naphthyl. The preferred heteroaryl groups are 3-earmyl, 2-thiapanyl and 3-pyridyl. Preferred cycloalkyls are cyclopentyl, cyclochromyl and cycloheptyl. Pseudo-chosen from methyl, ethyl, n-propyl, iso-diyl, n-butyl, cyclohexyl, benzyl, p-fluorobenzyl, p-aminophenyl, p-C-bromophenyl, p- Iodophenyl, p-hydroxyphenyl, p-methoxy.phenyl, 1-naphthyl 2-naphthyl, 3-indolyl, 2-thienyl, and 3-pyridyl. iUM can only be made by Benji and cyclohexyl -12- This paper size is applicable to China National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page), binding

XW 4 3 42-6 t A7 B7 V. Description of invention (1Q) It is better to choose. (1? 1) 111 (1? 2) (1? 3) 1 &quot; (: 11 ([: [12 | {4) (: 0- can be derived from an example of an amino acid residue is phenylalanine , P-fluorophenylalanine, p-chlorophenylalanine, p-bromophenylalanine, p-iodophenylalanine, tyrosine, p-methoxyamphetamine, 1-naphthylalanine, 2-naphthylalanine Acid, tryptophan acid, / 3-2-thienylalanine, / 3-3-pyridinealanine, ot-aminobutyric acid, n-valine, n-leucine, leucine, and cyclohexylpropylamine For compounds with high gastrointestinal motility, the preferred amino-terminal amino acids are L-phenylalanine, D-phenylalanine, L-cyclohexylalanine and D-cyclohexylalanine-position 2 The A group at the second position of the A group is an amino acid which is an L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid. L-_aliphatic aliphatic and alicyclic amino groups Examples of acids are L-valine, L-isoleucine, L-leucine, L-norvaline, L-norleucine and L-cyclohexyl reamine. Preferred A groups Amino acids are L-valine, leucine, and L-isoleucine. Position 3, group B. The group B at position 3 of the polypeptide is L-proline Acid or L-alanine amino acid. For the compounds with high activity of S-kinin receptor antagonists, the preferred β-amino acid is L-proline. _ Position 4 5, D-based printed by the Central Standards Bureau, Machining Consumer Cooperatives (please read the precautions on the back, and then fill out this page) The D group at the 4th position of the peptide is a lipophilic aliphatic or cycloaliphatic amino acid. L-stereoisomers of amino acids. Examples of lipophilic aliphatic and cycloaliphatic amino acids are L-isoleucine_, L-valine, L-θ amino acid, L-n-valamine Acid, L-n. Leucine and L-cyclohexyl alanine. Better D-based amino acid The paper size is applicable to China National Standards (CNS) _A4 specifications (210X297 mm) 43 4201 A7 _B7 _ V. Description of the Invention (11) is L-isopropylamine, L-leucine, and L-cyclohexylalanine. At the 5th position, the n-group at the 5th position of the n-peptide is an aromatic, lipophilic aliphatic, alicyclic Amino acids of L-stereoisomers of the Group Amino Groups. Examples of aromatic, lipophilic aliphatic &amp; cycloaliphatic amino groups are the residues derived from: phenylalanine, p-fluoro Styrene Acid, p-gas phenylalanine, p-bromo phenylalanine, p-iodophenylalanine, tyrosine, p-methoxyphenylalanine, pernaphthyl alanine, 2-naphthyl alanine, leucine and cyclic Hexylalanine. The preferred IE-ylamino acid is 2-phenylalanine and -cyclohexylpropionate. At position 6, the amino acid at position 6 of the L-threonine polypeptide bond is threonine. The 7th position, the F group. The F group at the 7th position is an L-stereoisomer of an aromatic or heteroaromatic amino acid. Examples of aromatic and heteroaromatic amino acids are casein Amino acid, phenylalanine, p-methoxyphenylalanine, glutamic acid, tryptophan, lu-2-thiophene alanine, and glutamine-3-D than pyridine alanine. Preferred p-based amino acids are L-tyrosine, L-amino acid and L-phenylalanine. Position 3 · G group / The G group at the 8th position of the polypeptide chain is glycine or D-alanine, and M glycine is preferred. · '· Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The 9th inspection, the 9th position of the fluorenyl peptide is L-glutamine / acid or L- The amino acid of glutamine is amine, and ML-glutamic acid is preferred. -The 10th position, the L-leucine standard of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4342 # 1 A7 B7 V. Description of the invention (12): •. * The amino acid at position 10 of the peptide is L-leucine. At the eleventh position, the I group at the eleventh position of the polypeptide is an amino acid of L-glutamine, L-glutamic acid, or alanine. Preferably, the depleted I-based amino acid is L-glutamine and the L-alanine J-based polypeptide. The J group in the polypeptide may be a direct link between the yl group and the -HH- group, or may be selected from Z, Z -Leu, Z-Leu-Gin, Z-Leu-Gln-Glu, Z-Leu-GLn-GIu'Lys, Z-Leu-Gln-Glu-Lys-Glu, Z-Leu-Gin-Glu- * Lys- Glu-Arg, Z-Leu-GIn-Glu-Lys-Glu-Arg-Asn, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys, and Z-Leu-Gln-Glu-Lys-Glu -Ar'g-Asn-Lys-Gly, and M is preferably selected from the following groups: Z-Leu, Z-Lw-Gln-Glu, Z-Leu-Gln-Glu-Lys ^ Glu ^ 'Z- Leu-Gln_Glu, Lys-Glu-Arg-Asn, and.

Z-Leu-Gln-Glu-Lys-Glu-Arg-Asrt-Lys-Gly. Z group is an amino acid selected from the group consisting of: arginine, D-arginine, D-same, arginine, D-lysine, D-ornithine, D-2,4-diamine Butyric acid, D-glutamine, D-asparagine, amine and D-alanine, and the system can only be selected from sporadic acid, D-arginine, D-glutamine and D-alanine The preferred Y position is 12 '. When the J group in the polypeptide is an I group. When directly linked to the -HH- group, the polypeptide is a dodecapeptide and the amino acid at position 12 is the C-terminal portion of the polyamidine. , -15- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 2 ~ 7 mm) ('' 'Pack-(please read the notes on the back and fill in this page) 1- °

/ 1U 4 3 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (13) '-N Η-* C H (C Η 2R 5)-R 3. When the J group is a 4 bond and the 1 to 2 and I 3 groups at position 1 of the polypeptide are hydrogen, the amino acid at position 12 has the [) configuration. The group is preferably an aminoalkyl group having 1-3 carbon atoms or a guanidinoalkyl group having 2-3 carbon atoms, and is preferably selected only from a group containing guanidinoalkyl groups having 2 or 3 carbon atoms. . More than aminoamino alkyl groups are aminomethyl, 2-aminoethyl and 3-amino-n-propyl. Preferred carboalkyl groups are N-2-carboethyl and N-3-guanidino-n-propyl. The Re group is -COOH or -CONH2, and M-CONH2 is preferred. The preferred condition is that the amino acid of the C-terminal portion of the polypeptide of the specific embodiment is selected from the group consisting of arginine, D-arginine, lysine, D-lysine, D-ornithine, D- 2,4-diaminobutyric acid and D-isospermine are more preferred if they can only be selected from arginine, D-arginine and heteroamine. When it is a direct bond between the I group and the -NH- group, the Z group of the amino acid at position 12 is formed. As mentioned above, the Z group is pseudo-selectively selected from amino acids: arginine, D-arginine, D-isospermine, D-lysine, D-ornithine, D-2, 4 -Diaminobutyric acid, D-glutamine, D-asparagine and D-alanine. Preferably, the Z group is selected from only arginine, D-arginine, D-glutamic acid, and D-alanine. More preferably, the Z and ^ groups are D-arginine. When the Re and R3 groups at position 1 of the polypeptide are hydrogen, the amino acid of the Z group has a D-configuration. __ [.1 position-set 1 3 'When the polypeptide of the present invention is a thirteen peptide, the amino acid at position 13 of the polypeptide is the C-terminal portion -NH- * CH (CH2R.5) -Rs, but L or D configuration and may be selected from the group consisting of lysine, ornithine, 2,4-diaminobutyric acid, arginine and homospermine. 16- This paper size applies to China Gujiayufeng {CNS) A4 specification (210X297 mm) I ---.---- ic equipment-- (please fill in the notes on the back of the book to fill in this page) I,,-° 434261 Employees' cooperation with the Central Standards Bureau of the Ministry of Economic Affairs Du printed by A7 B7 V. Description of the invention (14)-. »'Amino acid, and ML-lysine or [)" lysine is preferred. When the multi-makeup of the present invention is larger than thirteen peptides, position 13 The amino acid is glycine. 'Position 14 When the polysaccharide of the present invention is a tetradecapeptide, the amino acid of peptide 14 is 0 terminal moiety -K-* (: Η ((; Η2ΙϊΕ )-[ϊ3, which may be in the l or D configuration and 系 is selected from the group consisting of glutamine, lysine, ornithine, 2,4-diaminobutyric acid, arginine and isarginine, and It is preferably selected from the group consisting of: L-lysine, lysine, L-glutamic acid and D-glutamic acid. When the polypeptide of the present invention is longer than the tetradecapeptide When the amino acid at position j 4 of the polypeptide is L-glutamine. Position 15 When the polypeptide of the present invention is a fifteen peptide, the amino acid at position 15 of the polypeptide is 0 and the terminal part may be 1 or D conformation. Type and may be selected from the group consisting of lysine, ornithine, 2,4-diaminobutyric acid, arginine, and homospermine, and 丨,-lysine or D-lysine When the polyhumerus of the present invention is longer than the fifteen peptide, the amino acid at the 15 position is L-glutamic acid.

J position 16. ^ When the polypeptide of the present invention is sixteen 呔 i the amino acid at the 16 position of the polypeptide is the C-terminal portion -NH- * CH (CH2..R..5i-Re, may be l Or D configuration, and may be selected from the group consisting of lysine, ornithine, 2,4-diaminobutyric acid, arginine, and homospermine, while ML-chloramine. Or D-chloramine When the polypeptide of the present invention is longer than the hexadecide peptide, the amino acid at the 16 position of the polypeptide is -17- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ------- --Install-- (Please read the notes on the back and fill in 4 pages)

MJ order 4342g1 Consumption cooperation between employees of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of invention (15). '.. * * is L-lysine. 'Position 17 When the polypeptide of the present invention is a seventeen peptide, the amino acid at position 17 of the polypeptide is the C-terminal portion -HH- * CH ((rH2Rs) -Re, which may be in the L or D configuration, and may be H is selected from lysine, ornithine, 2,4-diaminobutyric acid, arginine and homosaccharic acid, and K L-lysine or D-lysine is preferred. When the polypeptide of the invention is longer than the seventeen peptide, the amino acid at the 17 position is L-glutamic acid.-Position 1 δ When the polyfluorene of the present invention is an octadecyl peptide, the amino acid at the 18 position of the polypeptide is the C-terminal Part of -HH-eCH (CH2Rs) -Re, may be L or D, and may be selected from the group consisting of lysine, ornithine, 2,4-diaminobutyric acid, arginine and the same Arginine, M is preferably selected from the group consisting of: lysine, D-lysine, L-spermine, and D-spermine. 1. When the polypeptide of the present invention is longer than the octapeptide, The amino acid at position 18 of the polypeptide is L-arginic acid. Position 19. When the polypeptide of the present invention is a nineteen peptide, the amino acid at position 19 of the polypeptide is j. 'C-terminal moiety-NUfHCiURs) -! ^, Which may be L or D configuration * I. _ can be selected from the group consisting of lysine, ornithine, amine, 4-diaminobutyric acid, and arginine Is the same as spermine, while M L-lysine is better than D-lysine. When the polypeptide of the present invention is longer than the nineteen peptide, the amino acid at the 19 position is L-asparagine. ·· Position 20 This paper is used in China National Standard (CNS) Α4 size (2 丨 0 × 297 mm) (Please read the precautions on the back before filling this page) Order

AV 434261 ^ The central standard of the Ministry of Economic Affairs prints A7 B7 for employee consumer cooperatives V. Description of the invention (16) '.. * * When the peptide is composed of 20 amino acids | The amino acid at the 20 position of the peptide is C- The terminal part, which may be in l or D configuration and may be pseudo-selected from lysine, ornithine, 2,4-diaminobutyric acid, arginine and homospermine, and from L-ionine Or D-lysine is preferred. When the polypeptide of the present invention is longer than 20 amino acids, the amino acid at the 20 position of the polypeptide is L-lysine. Position 21 When the polypeptide of the present invention is composed of 21 amino acids, the amino acid at position 21 of the polypeptide is the * C-terminal portion, -NH- * CH (CH2RS) -Re, which may be in the L or D configuration. Type, and may be selected from the group consisting of heterocyclic amino acids, ornithine acids, 2,4-diaminobutyric acid, arginine and isoarginine, and preferably L-lysine or D-lysine . When the polypeptide of the present invention is longer than 21 amino acids, the amino acid at the 21 position is glycine. ^ Position 22 The amino acid at position 22 of certain polypeptides of the present invention is the C-terminal portion of the polypeptide, -NH- &gt;! = CH (C 丨 URe) -Re, which may be in the L or D configuration, and may be Is selected from the group consisting of glutamine, lysine, ornithine, 2,4-diaminobutyric acid, arginine, and homospermine, and M is only available from L-heteroamine, phosphonate Among them, L-glutamine and D-glutamine are better. Amino acid at one end * -NH- * CH (CH2R5) Re residue at the C-terminal position of the polypeptide of the present invention, -HH-eCH (CH2R s)-Rg is an amino group of Re derived from C-terminal carboxylic acid Acid, where (^ is -C00H or -19 — this paper size applies to China National Standard (CNS) A4 specification (210X297 male sauce) --------- ", installed — (Please read the note on the back first Please fill in this page again for matters) -5 434261 Printed by the Consumer Cooperatives of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs A7 B7 V. Invention Description (17 -CONH2-K -CONHs is better. The definition of RB is as above. Means cyclic hydrocarbon radicals containing 5-7 carbon atoms. Examples of suitable cyclic hydrocarbon radicals are cyclopentyl, cyclohexyl and cycloheptyl. The term &quot; halogen &quot; as used herein includes 4 kinds Halogen is better than K. In a preferred embodiment, the compound of the present invention is selected from the group consisting of: κ-Ρ + τί-ν * ί * ΡΓ〇Ί 1 t * P + i * -Thr'Tyr-G t yG t u-Leu * C t n-〇-Arj-LeU'Gt n * Lyi-Gtu * Arg-AinTLyi-Cty-Ctn-OH; H-Ph »-V * l-Pro-I tf * Phe- Thr-Tyr-Gty-GIu-Ley-Gln * D * Arg-Lec-Gljvly »-Clu-Arg * Atn * Ly * 'Cty * Cln-MH2; H-Phe-Vil-Al i-ne-Phe-Thr'Tyr-Cty-Clu-LttJ-Ctn-O-Arg-Leij-Gtn-Lyi-Clu-Arg-AAn'Lyi-Gty-CIn-OH; Η * ΡΛ * -ν · ΙΆΙ · -Ι le-Phe'Thr-Tyr-Cly'Clu-Letf-Cln-O-Arg'L ^ u-GLn-Lyt-Gt ^ Arg-Ain-Lyt ^ Gty-Gln-MHj; H * P1ie * V * l -Pro-ne-f ^ e-Thr'Tyr'Cty-Glu-Leu-Ctn-D-Arg-HHj; H * Phe-Vtl * Pro-1 t * -Ph * 'Thr * Tyr-Gly- G tu-Leu-Cln-O-Arg-Leu-GLnOH; I IfWie-Thr-Tyr-GtyGtu-Leu-Gln-O-ArB-Leu-GtnOH; H * Phe-V * l * Pro-1 le-Phe ^ Thr-Tyr-Gly-Ctu-L * u-Ctn-D * h-Arg-Leu-GLn-OH; H-Phe-VaL-Pro-I te-Phe-Thr ^ Tyr-Gly-Glu-lw- GlnO-Lyi-Lw-GL'n-OH; j ** · 'K-Phe-V * t-Pro-I l ^ -Phe-Thr-Tyr-Cly-Clu-Ceu ^ Ctrv-D-Orn-Leu -Cln-OH; H-Ph «^ V» L-Pro-ne-Phe-Thr'Tyr-Gty-filu-ttu-Gln-D-Dab * ltu-Gln-OH; H-Phe-V * l- Pro-1 l «-Ph * -Thr-Tyr-Cly-Glu'Ley'-CLn-D * Gin * Leu *, GlnOH; \ K-Ph * -V * l-Ppt &gt; -I It-Phe-Thr ^ Tyr-Gly ^ Glu-Ltu-Gln-D'Ata-leiiOln-OM; K ', Ph * -Vel-Ali-1 l «* Ptie-Thp-Tyr * Cly ~ GlU &quot; L * u-rGln-D &quot; Arfl--L * iJ-Gtn * OH; M-Phe * V »t-? Ro-L« j-Pht-Thr-Tyr-Cly-Glu-Leu-Cln * D-Ar5-Leu-CLn-0H ; H-rtit * Val- ^ ro * n # -Cha-Thr-Tyr-Gty-Clw * Ltu-Gtn-〇-Ara: L * u-GlivOH; — K-rti * -Vil-Pro -Il ** Pti * -Thr-Fftt-Cly-CtU'L * u * Cln-D-Arg * LtueCln * OH; K-Ph * -yal-fre * I le-Ph * ^ ThP-Tyr-0- AU * ClueL * u-Gtn-D-Arg-Ltu-Cln-OH; K-Pht-Vil-Pro-I I # * Ptv «-Thr-Tyr *-&lt;! Ty ~ Clu: -L * u * Ala * D-Ar5-i * u * Cln * 0H; Η-Μι · -1 · α-ΡΓ〇-ΙΙ * -Ηι «-ΤΗΓ * Τγτ-βΙιτ-ώΙί * 1 ·« Όΐη-ΰ-ΑΓΒ-ί Α-βΙπ-ΟΗ; H-Pt »# ^ Vit-? Ro-Il * -Phe-Thr * Tyf'filyGlu-L * ij'Ctn-D-Ara-Ltu-Cin * NM2;

〇i-We) -Wi # * V * l-Pro-Il * -Pti * -Thr-Tyr + ClyGLu-LeyGln-D-Arg-Leu ~ Gtnm2J &lt; Η «2 * Ο * ΡΚ · -ν · 1 -? Γό * ϊί * -Μϊ * -ΤΗρ-Τ &gt; τ-01γ-βΙαΊ &lt; κι- &lt; ΪΙη-0 * ΑΓ9-1 · υ * ίΙη-ΜΗ2;) _ V · l-Pro_ ϊ l »* Pii ., Thr-Tyr · G l yG 【ii_ L * u · G l η · D · Απτ · L tu-C ln * UH2; -20- This paper size applies to China National Standards (CNS) A4 specifications (210X297) Li) (please read this page and then fill in this page)

434211 kl B7 V. Description of the invention (18 Printed by i-Pht-V * l-Pro-n * -Ph * -Thr-Tyr-GLy-Giu-Ltu-GLn-Dh-Arg -l * u * Gtn ^ HH2; K-Ptie-V * t-Pro-n * -Phe-Thr-Tyr-Gly-Gtu-t.tiJ-GLn * DL / s-Leij-Gln-NH2; &lt; -Ftie-V * l-Pro-I t * -Phe-Thr-Tyr-Gly-Glu * L * y'GLn-0-0rn-Leu-Gtn-HH2; tt-Phc-Thr'Tyr-Gly-Gtu -Ltu-Gln-D-Dah ^ Leo-GLn-HHs; K-Wi * -ViL-Pro-I te-Phe-Thr-Tyr-Gly-Glu-Leu-GlivO'Gtn-Leu-Ctn-HHj; I -Ph * -V * l-Pro-Il * -Pht-Thr-Tyr * GlyGlu-L * u- (iln-D'ALe-L «j-Gtn * &gt;IH2; -Ph« -Vet-Al * -Itt-fh «-Thr-Tyr-CLy-Ctu-L * w-Glr-0-ArB-LtiJ-Gln'HH2; I-Ph« -VtL-Pro-L »u-Ph« -Thr ^ Tyr- Gly-CtU'L * u-Gln-0-Arg-Leu-Ctn-MH2; i-Ph * -V * l-Pro-Ilt-Ciu-Thr-TYT-Gly-Gtu-L * g-Cln-0 -Arg-t.tu-Cln-MH2; I'Ph * -V * t-Fro-Il «-Ph * -Thr'Phe-Gty-Gtu-L» u-Gln-0-Ara-Le〇'Cln -MH2; Mi ^ he-ViL-Pro-Ite'Wif'Thr'Tyr ^ O-Ati-Glu-Ltu-Ctn-D-Arg-Leu-Gln-MHs; M-Ph * -VaL ^ Pr〇 ^ l le-Pht-Thr-TyT-Gty-Ctu-L * u-Al * -0-Arg-LetJ-GLn-MH2; l-Phe-Lw-Pro *! lt * Ph * -Thr-Tyr-Gty-Ctu -t * u-Gtn * 0-Arg-Leu-Gln-.kH2; M-ph * -Vit ^ Pr〇-IU * P + l * -T hr'Tyr-Cty'Ctu-LwGLn-D-Apy-LttJ-Lys-HH2; M-0-Ph € -V »l-Pro-Ilt-Phe-Thr'Tyr-Gly-Glu-L (ftu-GLn -D-ArB'LeuOtn-OH; M-Ch * -V «t-Pro-llt-Pti * -TKr-Tyr * l: ty-GlU'Leu-Gln-D'Arg-Leu-Gln-OH; M -Pht-Vit-Pro-n * -P + ie-TKr-Tyr-Cly-Glii-Le4-Ctn-D-Asn-LwJ-Gtn-OH; MD-Ph ** V »t-Pro-H» * f &gt; h * -Thr-Tyr-Gly-Glu-Leu-GLnO-Arg-leu-Gln-HK2; W-Ch * -Vit-PrO'Ue-Pti * -Thr-Tyr-Gly'Gtu-L * u -Gtn-D-Arg-L «j-Glrt * WH2; M-Phe-Vil-Pro-nt't ^ f-Thr-Tyr'Gty-Glu ^ Lw'Gtn'O-Asn'LwGLn-MHz; M -Ph * -V * t-? Ro-I l * -Ptit-TKr-Tyr-Gly-Glu-LturGtn-D-Arg-LttJ-D * Cln'MH2; ji H-Mi «-Vit-Al *- Ilt-Ptt * -Thr * Tyr * Cty-Glu-Ltii * Ctn-0'Arg-HH2; I-Phe-Vil-Alj-Ii «-Pti * -Thr-Tyr-GLy-CLu-Ltu-Gtn-D -Arg-Ley-Gln-OM; * A It-Pht-Thr-Tyr-fily'Glu-Leu-ClnO'Arfl-Leu-Gln-OH;! T * -Pht-Thr-Tyr'Cty-Ciu-Leu -Gln-0-Arg-Leu-6ln-OH; (H «3ii +)-Ptie-Val-At * -Il *-? Hi'Thr-lVr-Gty-Ctu-Leu-GLn-D-ArB-Leu * GlnOH; Ι-Μι * -ν * 1-ΑΙΐΊ · υ-^ «* ΤΚΓ-Τγτ- (ϊΙγ ^ 0ΐΐτί * υ-01π-0-ΑΓ3-ίίυ-αΐη-ΟΗ; l-? H # -V» L -Al * -nt-Ci «-Thr-Tyr-fity-Gtu-Ltu-Cln-0-Ara-Leu-Cln-OH; -Pti * -V * l-Ata-It * -Pht-Thr-Ptif-Cty-Ctu-L «u-Cln-D-Aru-Leu-Cln-OH; i ^ Pt &gt; *-Vil-At ** n ** fh ** Thr * TyT * D * Ati-Clu-Lw-Gtn * 0-Arg-L «j-Gln-〇H; -Wt &lt; -V» l-At * -He-fti «-T &gt; ir * Tyr-eiy-Clu-Leu-Ai * -D-Arg-L «U'Ctn-OH; lW» * »L # o-AU * ll» -M »*-Thr-Tyr-Clv-fitu-t« u-Cln-D-Arg * L * o-Ctn-OH; ο Loading-(Please read the precautions on the back and fill out this page) --6 The paper ruler is applicable to China National Standard (CNS) A4 specifications ( 210X297 mm) -21-434261 A7 B7 V. Description of the invention (19 Printed by DuPont Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs l-Pt «-Vil-Ali-n * -ft« -Thr * Tyr-Gty-Clu -L * u-filn-0-Ara-L * u-Ctn-HK2; (-JW) -Ph * -VEL-AL * -It * -rtw-Thr-Tyr-Giy-Ctu-i.tu-Gln -D-Ars-Leo-Gin-liH2; 〇tej) f *)-Wv «-V» l-Ali-Ii * -fh * -Thp-Tyr-fily-CLu-Leu-GLn-0-Arg-Leu -Cin-MH2; K-rt «* V * l * Al * -i # u-Pt &gt;«-Thr-Tyr-Cty * Cltj-L * «-Ctn-D-Arg-l« u-Cln-MH2 ; I-Ph # -V »l-Al ** ll * -〇M-Thr-Tyr-fity'Clii-L« i-Gln-D * AfTLtu-Cln-MH2; ^ WK-V * l-Alt- Il * ^ HwThr-Hw-Gly'filu-L # u-Cln-D-Arg-L * ii-Clrt-MH2; H-Phe ^ ViL ~ At ** I lt * Phe-Thr * Tyr-D * AtaOtu 'Leu-Gtn-D-Arfl'Letj- Gtn-MH2; H-fh «-ViL-Ala-Ile-Wie-Thr-Tyr-Ciy-Ctu-Leu-Al» -0-Arg-Leu-Gln-HH2; 1 H-Pti * -Lnj-Ala- Ht-phe-Thr-Tyr-Giy-Ctu-Ley-Glr »-0-Arg-LKi-Cln * i &lt;K2; K-Rh * -V * l-Al * -Ilt-Phe-Thr-Tyr &quot; Gly -Clu-Leu-Gtn-D-Arg-L «i-Lys-NH2; HD-Pti * -Ytl-Ali-Ilt- ^ he-Thr'Tyr-Gly * Glu-Ltu-CLn-D-Arg-L »Ii-Gln-0«; K-Ow-Vit-Ale-I Lt'Ph * -Thr-Tyr-CLy * Glu-L * u-Gtn-D-Arg-Leu-Gln-OH; H-Ph « 'V »lP * lI L« -Ptie-Thr-TyT-Cly-Clu-Leu-Gtri * Arg-leu-Gln-OH; (ί-D-Phe-Vil-Atm-I t *'-Phe-Thr 'Tyr-Gly-Glu-Leu-CLn-0-Arg-Leu-Gtn-HH2; • t · *! · H-Oi «* V« L4At «-l te-Ph» -Thr-Tyr-Cty-GLu -Ltu-Gln-D-Arg-L * u- {itn-MH2; one H-Pt «-Vil-Pit-lit'Ph * -Thr * Tyr-Cty-Glu-Ltu-Gln-Arj'Ley- Gln-MH2; &lt; ·. H-Ptw ^ Vil * &quot; ΑΙλ * Ι l * -Phe-Thr-Tyr-Gty-GLu-Leu-Ctr) -D * Arg-Leu-D * Ctn-iiH2; &lt; KM «)-Ph * -Vil-Al * -Ilt'fhe'Thr-Tyr-Gly-Ctu-Leu-GlnO-Ara-LeuO-Cln- * iH2; Lt-Ph * -Thr-Tyr * Gty-GlU 'Ltii-Gla-0-Ar9-Leu-D-Gin-KH2; (K &lt; 3) i +)-Wi * -ViL-ALi-Ile-Phe &quot; Tiir-Tyr-GlyGtu-Lty-GLn-〇-Arg * Leu-〇-Gtn-MH2 ;, Oi-HtJ ^ Pht-Vel-Pro-Ile-Phe- Thr-TyrOty'GtU-Lcu ^ Cln-O-Arg-Leu-O-Ctn-HHs; CMe2H) -Pht-V * L-Pro-n * -Ptie-Thr-Tyr-Gly-Glu'LetJ * GLri- 0-Arg-Leu-0-Cln-NH2; 〇 (e3H *)-Phe-V * L-Pr〇'I t «-PKe * Thr-Tyr-GLy-Glu-Leu-Gtn-〇-Are * Leu -D-Gtn-HH2; 〇 (-H «) * Ph * -Vil-Ali-lle-Phe--Thr-Tyr-Cly-Glu-Ltu-Gin * 0-Arg-Leu-Ly» -liH2; &lt; M «2i〇-Ph» -V * L-Ai ** l tt-Ph * -Thr-Tyr-Cly-CliJ-Leu-Cln-0-Arg-Ltti-Ly * -WH2; (M «3) i + &gt; ^ Phi-ViL-ALi-I le-Phe-ThrTTyr-Gly-Gtu-Leu-Gln-〇-Arg-Leij-Lyi-MH2; () iH «)-Ph« * V * l-Pp 〇-Il ** Phe-Thr-Tyr-Gty-Glu-Ltu-GLn-D-Ar〇-leij-Lyi-NH2; («« jMi ^ Ptie'ViL- ^ ro-Ut-Phe-Thr-Tyr- Gly-GLu-Leu-Gtn ^ D ^ Arg'Leo-Ly ^ -HHi; O * «3) i *)-Ph« -V * l-Pro * It * -Phe-Thr-Tyr-Gly-Giu- Leu-Cln-0'ArB'teu-Ly * -MH2; &lt; H-«* &gt; -Ph * -V * l-AU'IU-Ph * -Thr-Tyr-CLy-CLu-Leu &gt; Gln- 0-Arg-Leu-0-Ly »-« H2; (H «2l〇-Mw-V * l-Ati-n * -Ph * -Thr'Tyr-Gty-GLu-Leu-Gln-0'Afg ' Leu-0-Ly »-HH2; Ⅰ 22-This paper size is applicable to China National Standard (CNS) A4 (210X297 mm). Please note the following details: 43426 A7 B7 V. Invention Description (20

(鼢 3 «+) · puff * · ν · 1-Μ ·, &lt; H« 2i〇-Ww-V * 卜 ΡΓΰ-i (He3X +)-Ph * -Vel-Pro- &lt; H «2«) -Ph * -VaL-Al · (We ^ J-Ww-Vst-AL Section M · ν · 1 ·, Γ〇le-rPhe-Thr-Tyr-Gly-GLu-Leu-Cln-D * Arg * CeiJ- D-Ly »-HH2; * -Phe-Thr-Tyr-Gly-GLu-Leu'Gln-D-Arg-Ltu-D * Lyt * HH2; r-Pht-Thr-Tyr-Cty-Clu-Leu-Gln -D-Ars-Leu-D-Lv * -MH2; l # * Ph * -Thr-TYT-Gty-Clu-Leij-Gln-0-AfQ-i.eu-0-LYt-HH2; • -fhe- Thr-Tyr-Gly * filu-L «j-Atft-〇'Arg-Leu * Gtn-MK2;» -Wrt-Thr * Tyf-Cly-Glu-I.eu-AEa-D-Ara-LttJ-GLn- MH2; lt * Phe-Thr-Tyr-CLy-Glu-Leu-ALfc-D'ArHM.tu-Cln-MH2; Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs &lt; H «3 * 〇-Ph * -V * i-Pro CM «^)-Ph * -V« l-AL * (M «2N) -Ptie-V» t-Pro (Η · 3Η +) · Ηι * -ν · Bu Pr. -(M-Wt) * f4it-V »L-AU &lt; K« 2H) -Phe-ViL-Ali CH «3M +)-Wie-Vei-Ali 〇l-Me) 'Hi«' Vil-Pro (H * zM) -Ph * -Vit-Pro (K «3M *)-PH« 'ViL-Pro (K- »U) -Ph« -VaL-AL * (H «3i (+)-Ph« -V * t-At 〇i-Me) -PKe-V * l-Pr〇 («e2M) 'Ptie-y * t-Pro (He3« *)-Phe-V * l-Pro &lt; HM *)-Phe- ViL'Al * («C2N) -Ph * -V * l-Ati &lt; Me3M +)-Ph« -V * t * AU 〇 (-«c) -Phe-Vil-Pro- •• HwThr-Tyr-Gly -CLti-L * ii-Al_.DA 「BL * tj_Glft-HH2; t-Wi * -Thr-TyT-Cly-Ctu-Leu * At» 'D'Arfl'Leu-ClrY-iiH2; lt-Pht-Thr -Tyr-Gly-Ctli-Leu-AU-D-ArB * L * u * Gln-MK2; * -WwThr-Tyr-Gty-Gtu-Ley-At * -0-Ar9 * Leu-0'Cln-MK2; * 'Ph * -Thr-Tyr-Gly-Clu-L * U'At * -D-Are ^ Leu-0 * Cln-i &lt;H2; lr-Phe-Thr-Tyr-Cly-Clu-Leij-Al » -0-Ars-L * uD * Cln ** (H2; • -Ph * -Thr-Tyr-Cty-Clu-iru-Ai * -0'Ary-Leu-D-Cln-MH2; e-Ph *- Thr-Tyr-Cly-Ctu-Leu-Ala-0-Ar5-Leu-D-Cln-WH2; l ^ phi'Thr-Tyr-Cly-Clu-L ^ fru-Ate-D-Arfl-Leu-O ^ fitn-MHj; ** phe * Thr ^ Tyr-Cly-Ctu-LeiJ-Al * -0-Arfl-Leu * Ly »-iiH2; e-Phe-Thr-Tyr-Cly-C [u-Ltfu-AieO * ArB * Leu ^ Lyi'MH2; tt * Phe * Thr-T &gt; r-Cly-CtutaL «j-Ala-D-Arg-Leu-Ly * eNH2; • Ph * -Thr-Tyr-GtyGl u_LctJ-Al 麈 Hrfl-Leu * Lyi-NH2; * -Phe-Thr-Tyr-Cty-Clu-Leu-Ala-D-Ara-LeiJ-Ly «-HH2; lt-Ph * -Thr-Tyr-Cly- Glu-Leu-AL * -0-Ars-Leu-Ly »-liH2; i / 1 I. *-) &Gt; he-Thr * Tyr * Cly-Glu-Leu-Ata-D * Arg-leii-0- Ly * -KH2; fpht'Thr-Tyr-Gly-Glu-Leu-Att-D-Arg-Ley-O-Lyt'KHz; te-Phe-Thr-Tyr-Gly-Clu-Leii * Ata-O ^ ArB -Leu-D-Lyi-XH2; (-fhe-Thr * Tyr * Gly'Clu-Leu-Ala-0-Arg-Leu * 0-Ly «* MH2; t-Ptie-Thr-Tyr-Giy-GLu * Leu-Aia-0-Ar3'leu-D-Ly * 'WH2; It-Pht-Thr-Tyr-Gly-Giu'Leu-Ale-O-Arg'Ltti-D-Lyi-WHj; * -Mie-Thr 'Tyr-Cly-Clu-Leu-Gln-0-Arg-NH2; t-Phe-Thr-Tyr-Cly'Ctu-Leu-Ctn-O-Arg-HHj; l * · yesterday e, Thr, Tyr-Gly_Glu -Leu, Glr ».0-Ara-MH2i * -Wi * -Thr-Tyr-Gty * Ctu-Leti-Cln-D-Apg-HH2; 23-This paper; ^ degrees are applicable to China National Standards (CNS) A4 Grid (210X297mm) (Please read the notes on the back and fill in this page) 43421 A7 B7 V. Invention Description (21 λ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (M «2ii3-Ph * -V * t-Pro-lU-Phe-Thr-Tyr'Gly-Glu-leu'Gtn-〇-AfB-HH2; &lt; H «3 ^ +) * Ptit-V * LePro-I le-Phe-Thr-Tyr- Gly-CLu'Leu-GLn- 0-Arg * HH2; 〇iH〇-Ptie-V * l-Pro-He-Phe'Thr * Tyr-Giy-CLu-Leu-Ala-0-Ar.g-MH2; &lt; Me2 * 〇-Phe- V * l-Pro-lU-Phe-Thr-Tyr'Gly-Ctu-Leu-Ata-D-Arg-MH2; &lt; Me3X *)-Ph * -V «t-Pro-lt *-? He-Thr -Typ-Gty-Gtu-Le) j'AU-D * Arg-WH2; D-Chi-Vil-ALi-Ile-Ph &lt; -Thr-Tyr-Gty'CLu-Laj-At »-0-Arg-Liij -0-Lyi-HH2; 〇i-H &lt;) 'Ptie'Vtt * Pro-lle-Phe-Thr-Tyr'Cty-Glu-LwGln-Arg-MH2; 〇 ^ 2 &gt; 0 * Μτ * · ν · bu Pro-IU-Phe-Thr-Tyr_Gly-Glu-Leu-Gln * Ar9, iiH2; (M «5« +)-Ptie-VtL-Pro-n * -f &gt; h * -Thr-Tyr-Gly-Gtii * LttJ-Gln-Arfl-HH2; 〇IK «)-Wv4-ViI-? Po-! L * -Ph * 'Thr-tyr-fily-Ctu-LKJ-Ctn-0-Artt + HH2; I (H * 2 * 〇-Wi * -V »l-Pre'il« -Ph * -Thr-Tyr-Gty-Clu-t. * Ii-Ctn-0-ArB'iiH2; * (K «3M +) * W« -Vtl -Pro-Il * -Ph * -Thr * Tyr-Cty-Ctu-L «J-Gtn-D-Ari-iiH2; 〇iH«)-Pht-V * l-ALi * ILt ^ *-Thr-Tyr- Cty-Clu-Ltu-Gln-Arfl-HH2; (M «2li) 'Wvt-Vil-Atm-It« -Ph * -Thr * Tyr-fily-Clu-Ley * Cin * Arg-liH2; &lt; K * 3it +)-Ph * -Vil-Al »* U * -Mie-Thr-TyT'Cty * Ctu-Leu'Gln-Ari * MH2; &lt; K * H *)-Ph # -V» l-Ali-H «-Ph * -Thr-Tyr * Cty-Clu-L * u-Gtn-0-Arf-HH2; First, (Mt2W &gt; -W ie * V * l-Ali-U * -Ptie-Thr-Tyr'6ly-Clu-LeuOln-D-Ar8-iiH2; f. (HeSM ^ J ^ WK-ViL-Ale-Il ^ Phe-Thr-Tyr- CLy-Clu-Lfti-Gln-O-Ars-tiHz; &lt; M * lte) -Pht-Vii'Ali-tl * -Mie-Thr-Tyr-Cly-iiLu-l * u-Ait-Ari-MH2; &lt; He2 * 〇-W »*-V * t-Al # -IU * rti # -Thp-Tyr-Cty * Clti-LtU'ALi-Arfl * liH2; &lt; H * 3Jr *) 'Pht * Val- AU-IU-Pt &gt; t-Thr-Tyr-CLy * Clu-l «u-Ati-Ar9- * iH2; (. (HK«)-^ h # -VtL-Pfe * Ut-Ph * -Thr-Tyr -Gty-Glu * L * ii-CLn-Arg-Leu-Ly *-) iH2; (Me2M) taW &gt; eV * L-Pro-I lt ^ Phe-Thp-Tyr-Gly-Gtu-Leu-Gtn-Arg -Leu-Ly »-MH2; &lt; W« 3K +)-Ptt * -V * l-Pro-Ut-Piie * Thr-Tyr-Gty-Gtu-Leu-Cln-Arg-Leu-Ly ** »H2; (MM) -Wi * -V * l-AU-lU-? H * -Thr-Tyr-Gty'Gtu-Leu-Gln-ArB-Leu-Ly * -MH2; (M € 2M) -Phe-V * l-Ati-I t * -M »€ -Thr-Typ- ^ ty-CLu-Lcti * Cln-ArQ``Leu-ly» -llH2; (K * 3K *) * Ph «* Yil-Ali-H * -Ph * -Thr-Tyr-Cty-GLu'Leu-Gln-Arg-Leu-Ly * -MH2; («-ikJ-Wit-Vit-PfO-Ile-rte-Thr-Tyr-Gly-CLu-Leu -AU-ArB'Leu-Lym ^ MHZ; &lt; Hf2 * 0 * Ph * -Vit-Pro-I l * -Ph * -Thr-Tyr-Giy-Glu-L * u-Ali-Arg-Leu-Ly »-LiH2; (H« 3M *)-? Ht * V «l-PP〇-! Lt-Ph * 'Thr-Tyr-Cly-Glu-Ley-AU-Arg-Leu * Ly»-) IH27 (-* i *)-Ph «-V * l-AU-lU * Ptie-Thr-Tyr-Gly-Clu-l * u-Al» * Arrltu-Lyi-MH2; One 24-This paper size applies to China Standard (CNS) Α4 specification (210X297 mm) (Please read the notes on the back and then fill out this page), printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 434261 A 7 B7 V. Description of the invention (22) t * -Phe-Thr-Tyr'Gty * Glii-Leu-Atf-Arg'LetJ-Ly »-WH2; (K« 34 * +) * ^ ** Vil * Al4 * n * -Phe-Thr-Tyr- Gly-GLu-lwj-A [a-Arsr-Leu-ly »'MH2; 〇i-Ke) -Phe-Yil-Pro-n *-? Tie-Thr-Tyr' &lt; lly-Clu-Leu'Gln -Arg-Lftu-D-Gln-MH2; (Η € 2M) · ^ β-ν · 1 · ΡΓ0 .: l * -ph * -Th ".Tyr.GlyGtu-Leu, GlrvA" g, Leu-D, GlrrHH2; (M «3M +)-? H * -ViL-Pp〇-I tf * Phe-Thr * Tyr-Gly-Gtu-Leu-Gln-Apg-Leu-0-Gtn-MH2; (« -Ke)- P + i * -VaL-Ati-tl * -Phe-TKr-Tyr-Gty-Gtu * Leu-Gln-Arg-Leu-D-GLn-HH2; ^ X «2 * 〇-Phe-V * i-Ai ·-! Te-Phe-Thr-Tyr-Gly-Giu-Leu-Gln-Arg-Leu-D-Gln-MHj; (»« 3M +) ^ Phe-V «L-Al»-! T * 'Wi * -Thr-Tyr-Gly-Glu-Leu-GLn-Arg-Leu-D'Gtn-NH2; (N-M &lt;)-Wi *,-YilTPrQ * l lt * Ph * -Thr-Tyr-Gly-GLu- Lr &lt; jA [a * Ars-Leu-〇-Gln-MH2; (KejNi- ^ he-Vtl-Pro-I l * -f &gt; h «-Thr'Tyr-Cty-Ctu-Leu-Ata-Arg» Lftu-D-Gtn-ilH2; (N * 3N +)-Ph * -V »L -Pro-Ilr-Phe-Thr-Tyr-ilty-Glu-Leu-Ale-Arg-Leu-D-GLn-MH2; (M-HO-Phe-Vil-AU.Ilir-PhtThr-Tyr-GtyHu-Lti ^ AU-Arg-Leu-D-Gln-MHS; &lt; K «i * ()-fh * -V * l-Ali-ne-? H« -Thr-Tyr-Gly-Glu-Leu * Ali-Arg- Lw-0-Glr »-» iH2; * nci 1 (Me3Ji +)-Phe-V * L-At * -I le-Pht-Thr-Tyr'Gty-Gtu-Leu'Ale-ArB-Leu ^ O-Cln -NHji and its peony acceptable addition salt. In each case, unless otherwise specified, amino acids are in the L-configuration. In a more specific embodiment, the compound of the present invention is selected from the group consisting of K, K., (M-KO-W ^ -VdrQ-UiPhe-Thr-Tyr-GlyGlu-Leu-GtrvD-AFfl.Leu'Gln -OH; &lt; «-H *)-Wit-Vil ^ p〇-Iti-Mi« -Thf'Tyr-Cly-6Lu-L «i-Gln-0-Arg-Ltu-Cin-WH2; 〇W2 * () -Pt »-V * L-? Ro-U * -M &gt; e-Thr-Tyr'fity * Ctu-Lttj-Gln-D-Arg-Leu-Cln-MM2; flutter ** V * L-Pr 〇 * ll *, Ph * -Thr-Tyr-GlyGlu-Leu-Gln-D-Arg-L # ii-Cln-HM2J (MK *)-Pht-Vil-AU-Ilt-Ph «-Thr-Tyr * Gly * Clu-ttu-Gln-D-Ar9-Ley-Cln-0H;

J &lt; Ht2 * l) * Wtt-y * l-Mt-Il * -Ph «-Thr-Tyr-fily-fitu-Leu-Gln-0 * Arfl-Leu-Gln-0H; (KtjX ^ J-Ww -Val-Ali-llfPh ^ Thr'Tyr'Cty-Gtu-leij-Gin-D-Arg-Leu-CtnOH; .1 (Μ- &gt; Ι «)-ΡΗ · * ν * 1-ΑΙ · ,,, ΪΙ * -ΡΗ «-ΤΚΓ-ΤγτΌΙ / -61υ-ίΛΐ-αΐη-0 * ΑΓί ^ ίβιι-01η ^ ΜΗ2; &lt; &gt; k ^)-Wi» -Vel-Ali * ll * -Mi * -Thr- Tyr-Ciy-Giu-L * u-Cln-0-Arg-L * y-Cln-liH2; &lt; K «3tl *)-Wie-V« l-Al * -n «-Phe * Thr-Tyr- Cty-Ctu-Leu-Ctn-D-Are-t. «J-(: tn-HK2; &lt; lf-K«) *? H * -V * l-Alm-ll * -Wie-Thr-Tyr- Gty-Ctu-LttJ-Gln-0-Are-Leu-0-Gln-MH2; (H * 2i〇-Pht-Vil-ALi-ll «-Ph« -Thr-Tyr- (ily-Clu-Leu-Gln -D-Arg-LeiJ-D-Ctn-MH2; &lt; H «3li +)-Ph« -ViiL-Al * -l tt-Ph «-Thr * Tyr-Cly'GlU'Leu * Gln-0-Arg- L «jD-Clrt-HH2; &quot; 25- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -------- () installed I — (Please read the precautions on the back first (Fill in this page again)

MJ,-* 434261 A7 B7 V. Description of the invention (23) The policy of employee consumer cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, L * -Phe'Thr'Tyr-Gly-Gtu-Leu-Gtn-0-Arg'Leu-D- &lt; * tn * NH2; (M «2 **) '^ *' V» l * Pro-Il * -f ^ fThr-Tyr-CLy-filu-LeiJ-Gln-0-Arg-L * uD-Gtn -MH2; (Me3) i *)-Ph * -V * l-Pro; nt-Phe-Thr * Tyr-Gly-GLu-I.eu-GtnO-Ar9 * Lwi &quot;D-GLn-MH2; I (WH *)-Ph * -VilfcALfn * -Pfit-Thr-Tyr-Gty * Glu-Leu-GLnO-Arg-Leu-Ly * -WH2; &lt; M «2 * O * Pht-V * l-At * -H ** Ni * -Thr'Tyr-Cly'Gtii-LetJ-GtrT-0-Ara * Leu-Ly *,-MH2; &lt; K * pi +) * Ph # -V »l-AU-It * -Ph * -Thr-Tyr * Gly-Gtu-Leij * Gln-0-Arg'LwLy * -liK2; &lt; H «^)-Ph« 'Vjil-Pro-ne'Phe-Thr-Tyr-Gty-ClU-leu- Gln-D-Arg-Liu * Ly »-MH2; (Ke3W +)-Wi * -V * l-fro-I te-Wie-Thr-Tyr-Gly-Glu-Leu-Ctn'D-Arg-Leu ^ Lyi -HHj; &lt; Μ * Κ «)-Ρίι · -ν * 1-Αΐ · -ΙΙ * -ΡΚί * ΤΜΓ-ΤγΓ-βΙγ-ΰΙυ-ίευ-01η-0-ΑΓ5-Ιίυ-0-ίν * -ΜΗ2 ; &Lt; Me2 »i) 'Ph * -Vil-Ali-Il *' Ph * -Thr-Tyr-Gty-Glu-Leu-Gtn-D-Arfl-leu-0-Ly» -MH2; (K «3H + ) -Phe-Vit-Al * -I tt-Phe-Thr-Tyr ^ Cty'Ctu-Letj-Cln-O-Ari-Lctr-0-Lyt-KH2; 〇 ('H «)-Ph * -V» L-Pf〇-ll « -Wi * -Thr-Tyr-Cty-Glu * Leg-Gln-0-ArB-Leu-D-Ly * -MH2; (Me2M) -Pt) *-V * l-Pro-H * -Phe-Thr- Tyr-Cly-Glu-Leu-Cln-〇-Arg-Leu-〇 ^ l.yi-MH2i (Me3) i *)-Ph * -Vil-Pro * Ut-Phe * TKr-Tyr-Gty-Ctu-Leu -CLn-0-Arg-Leti-D-Lyt-KH2; &lt; ^ ki) (MH *)-Phe-V * l-Al * -nt-Phe-Thr * TytL-Cty-GLu'Leu-ALa- 0-Arg-Leo-Gln-HH2; &lt; Kt2N) * Ph »* V * l * Ate * Ht-Phe * Thr-Tyr-Cly-Glu-Leu'Ala-0-ArB-teu-GLn-MH2; t '&lt; H ^ 3ii +)-Ph * -Vil'A (»-ll * -Ph« -Thr'Tyr-Gly-Clu-Leu-ALa-0-Arg * Lev-Ctn-HH2; (M * Ke )-? h * -V »l-Pro-ll» -Phe-7hr-Tyr-Gly-Clu-Ltii * Ala-0-Ara-Leu-Cln- &gt;iH2; CM * 2 * ()-Wi * -V »l-Pro-Ile-Ph * -Thr-Tyr-CLy-Glu * LeU'Ala-0-Arg-Leu-Gln-MH2; (He3 &gt; i +)-Phe-Vit-Pro * H * -Ptie -Thr-Tyr-Gly-Glu-Leu-ALa-E &gt;-Arfl-LiU'Ctn-MH2; (M-HcJ-Pftt-Vi ^ ALi-Ilt-Phe-Thr-Tyr-Ciy ^ Ctu-Leo-AU -O-Arg-Leu-D-Cln-MH ^; &lt; H «jl〇-Hit-V * l-Al * -H, ** Ph * -TKr'T &gt; T-Cly-alu-Leu-Al &gt; -D-Ar5-Ltu-〇 * CLn-MK2; {Ktjii ^ i-Wrt-VlL-Ali'nt-Phe-Thr-Tyr ^ Cly'Glu-Leu'AU'D-Arfl-Leu-O-Cln -iiHj; 〇li **)-Ph «-V * l-Pro * Ht-Pht-Thr-Tyr ^ Gty-Clu-leu-Al * -0-Arg * Leu-D-Cln * MH2; &lt; We2 *) 'W' * &quot; Vii-Pf〇-Itt * Pti * -Thr-Tyr-CiyClu * LeiJ-Ati-D-Arg-Leu-D * Clr &gt;-IIHz; &lt; H * j * i +)-Ph * -V »l-Pro * llt-Ph ** Thr-Tyr-GLy-Ctu-LetJ'Ale'D-Arg-Lwj-0-Ctn-lfH2; CM * W«) * Wt * -V * l-Al * -n «-Wv * -Thr-Tyr-Cty-GtirLtu-Ala-0-Ar5-Leu'Lv ** HH2; (M« 2 ^)-? MV »l-At» -U * -Pht-Thr 'Tyr * Cly-Glu-L * u-Al »-D-Are-Leu-Ly * -IIH2; &lt; H &lt; 5M +)-Ph # -V * l-Al« * nt-Ptw-Thp'Tyr- Cty-Clu-LetJ-Ati-0-Arfl-L * iJ'Lym-KH2; &lt; H-lK) -nw * Val-Fr〇-Il * -ft &gt; ** thr-Tyr-GLirfiLu-L «u * ALa-0-ArB-L «i ^ Ly ** tK2; 0 ** 2M) -Ph # -Vil * fro-IlfH» «-Thr-Tyr-Gly-Ctu-L # u * Ata-D-Arg -L * u * Ly ** KH2; (please read the notes on the back and fill in this page again) V-packed paper ruler and applicable Chinese National Standard (CNS) A4 specification (210X297 mm) 434211 A7 B7 5 Description of the invention (24) λ Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs &lt; H * pi +)-Ph * -V * l, Pro-IlfWi * -Thr-Tyr-Gly'Glii * Leu, Al *- D-Arfl-L * u-Ly »-KM2; &lt; MH«)-Hi * -V * t-Ati-Ht-Pht-Thr-Tyr-Cty'Gtu-Leu-Al * -D-Arg-Leu -D-Ly »-liM2; l ** Ph« -Thr-TyT * Cly-Glu * Leu-Al * -D-Arg-Lec-0-Ly »-MM2; (Η 3 ^ +) · Μι * · ν »1 · ΑΙ ·· I l *, Wi» -Thr-Tyr-Gty-iitLi-Leu.Al_-D-Arg-Leu-i &gt; -Ly »-MH27 CK-He ) -Ptie-V * t-Pro-Il * -Pti * -Thr-Tyr-Gty-GlU'LeiJ-AU-D-Arfl-Leu-0-Ly »-¥ H2; (HezMJ-Phe-Vtt-Pro -I it-Wie-Thr * Tyr-GLy-Glu-Lcu'Ata-D-Arfl-Leu * D-Ly * -MH2; (M «3X +)-Ph * -V» l * Pro * I l ** Ptie-Thr-Typ-i; ty-Gtu-Leu-Aia-D * ArB-Leii-D-Ly »-HH2; (H-Pte) -Ptie ^ Vtt-Ali-I l * -Phe-Thr-Tyr -Gty-Clu-Leu * GtnO-Apfl-MHj; &lt; He2 *) * ^ 1 * &quot; Vtt-ALi-Ht-Phe * Thr-Tyr-Gly-GlU'LeiJ-Gtn-0-Arfl-HH2; &lt; Κβ3Η *)-Ρίΐ € -ν * 1-ΑΙΐ * Π · -Μϊ · -ΤΚΓ-ΤγΓ * 0ΐγ-0ΐυ-1 ^ -01η-0-ΑΓ9-ΧΗζ; (KH *)-Ph # ^ V » L * Pro-Il * -W «-TKr ^ Tyr-Gly-Clu-Leu-Gln-D-Arfl-HH2; &lt; Ht2 * (&gt; -Hi * -V * l-Prd-fl * -fh« -Thr * Tyr-Gly-Clu-Leu-Cln-DTArBTMH2; (KejM ^ J-PhfVil-Pro-Ile-Phe-Thr'Tyr-Gly-Gtu-Leu-Gln-O-Arg-liHz; (KH «) -Ph * -V «l-Pro-nt-Ptie-Thr-Tyr-Cly-Glu-Leu-Al * -D-Ari3-HH2; (M« 2 * i &gt; -Ph * -ViL-Pr〇'I lt-Pii € -Thr-Tyr'Gly-Clu-Leii-Ala * 0-Arg- * iH2; (HijU ^ J-Pht ^ Vtl'Pro-Ile-Phe-Thr'Tyr-Giy-Glii-teu'Alfl -D-Arg-NH ^; &lt; IH *)-Ph * -VtL-P ro-H * -Ph «-Thr-Tyr1-Gly'Gtu'leu-Gtr \ -Arg-iiH2; &lt; Μ * 2 ^ ί ^ V * L-Pro- H # * Phe-Thr-Tyr ' Giy-GlurLeu-Gln-Apfl'HH2; (H * 3M +)-Ph * -Vil-Pro-ll * ^ Phe-Thr-Tyr-Gty-GlU'Leu-Gln-AraeHH2; (KM «)-Pti ** Vtt'Pro-Ht-Wie ^ Thr-TyT'Gly-Gli / -Leu-Ctn'D-Arg-MH2;, (Mt2M) -Ptit-V * l * Pra-It ** Phe-Thr-Tyr'Gty -titu-Leu-Gtn-D-Arfl''HH2; tH «3» &lt; +)-? h * -V * t-Pp〇-Il * -Phe-Thr-Tyr-Gly'Clu-Lcu-GLn -0-Arfl-HH2; il 〇lM «)-Fh * -V * L-Al ** Il * -Pht * Thr-Typ-Gly-iilu-Leu-Gln-Afa-HH2; (Μ · 2 ** ) ~ ^ · * Ν * Ι ^ Αΐ »Ί t« -Ph * -Thr ^ Tyr'Cly- &lt; * tu-Leu-Gln-Arg-HH2;,: j &lt; M «3 * i *)- Ph * -Vil-Ati-Il * -Ph * -Thr'Tyr-Cty-Clu-Leu-Ctn-Arg-HH2; tK-MtS ^ Phe-Vti-ALt-Ut-Phe-Thr-Tyr-Gly-Glu -Leu'Clri-O-Arg-MHs; &lt; Λ «2Κ) &quot; Μ« -ν · ΙΆΙ * -Ι t * -Ph ** Thr * Tyr ^ Gty-Gtu-Leii-Gln'D-Arg- KH2;) -Ph * -Vil-Al * M te-Wie-Jhr'Tyr'Cty-Ctu-Leu-Gtn-D-Arg'HHs; (M-Me) -Ph ** V * L-Ali-Ue -W »i * Thr-Tyr-Cty-Glu-LeiJ-Ati-Arg * MH2; (H« 2M) -Ph * -V * t'AU-lt * -Phe-Thr ^ Tyr '&lt;; ly- Ctu-Leti-Ate-Arfl-HH2; 0 * «3M +) * Ph» -Vil-AU * Il ** Ph «-Thr-Tyr-filyi'Ctu * L * U'A le-Arg-liHz; &lt; ll'H *)-Hw-Vil- ^ ro-Il »-Mw-Thr-Tyr * eiy-Clii-Leu-Ctn-Ar9-Lttj * Ly, i-MH2; this paper The scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 4342§t1 A7 B7 V. Description of the invention (25 λ CH &lt; 2i &lt; 3-W «-Vil-fro * n * -Wv« -Thr-Tyr- Cty-Clu-L «j-Gln-Ara-Leg-t.yi-i (K2; (« «3 * i +) '^' V * ie ^ 〇 * K« -W »*-Thr-T &gt; T -Cly-filu * Leu-GlnMrg-Leu-Ly * -iiH2; &lt; II-M #)-H «-V * l-AU-! Lt-Wt« -Thr-Tyr-Cty-Cly-Leu-Cln -Arg-L * tj-Ly »-HH2; CM * 3Ji +)-Ph # -Vit-Ati-Itt'Pt« -Thr-TyT-Cly-fitu'Leu-Ctn-Arg-Leu-Lyi-KH2; &lt; MH «)-Ph ** V * l-Pro-Ilt-Pf» «-Thr'TyT-Cty''Glu-LeU'Al ** Ar9-Lftj-Lyt- * K2; (H« 2i〇- « &gt; *-V »l * Pro-U * -ftMt * thr-Tyr * Cly-ttlti-L * u-At» -Ara'L »u-tyi-KH2; &lt; J ** 3M +) * ^ h4 -Vii-fro * IU-Ph * -Thr-Tyr-Cly'Clu-LwAia-Arfl-tty-Ly »* MH2; (B ^ HtJ-Wve-Vtl-Ail-Ut-Hrt-Thr ^ Tyr-Cly- Clu-Ltu-Ali'ArB-LwLyi-iiHz; CH # 2M) -Hw-V * l-AU * U * -WY «-Thr * Tyr-Cly * Ctu-L« u-At # * ArB-Leu- Ly * '| iHz; (M «3H +)-Phe-V» i-AU-Ilc-Ptve-Thr-Tyr * Cty'Glu-ieu-Ata-ArB-l.eu-Ly *-»iH2; &lt; W-Me &gt; »Phe-Vil * Pro-n * -Phe-Thr 'Tyr-Cly'Ctu'Leu-Gln-Ara-Leu-D * Gln- &gt;iK2; (He2M) -Phe-V «l * Pro-lU-Phe-Thr-Tyr-Gly-GlU'Ltu-Gtn -Ari-Leu-0 * Ctn- «H2; (Mej ^ J-Phe'Vel'Pro-ILi-Phe-Thr-Tyr-Cly-Glu-leu-Ctn-Arg'Leu-O-Gtn-HHZ; &lt; Jf-H «)-^ h * -Vtl * Alt-ll» -Pht-Thr-Tyr-Gty * Gtu-Leu'Gln-ArB-L «j-0-Gtn-) iH2; (H« 2K) -Phe-Vit'Al * -Ilr-Phe-ThrfcTyr-Gty-Ctu-Leij'Gln * Arg-Liu-D-Gln-liH2; (K ^ jW ^ J-Phe-Val-Ali'Ilt-Phe'Thr 'Tyr'Gty-Ctu-Leu- ^ tn-Arg-Ltu-p ^ Cln-iiHz; I (MM «)-f &gt; h * -Vil-Pro-n *' f &gt; he-Thr-Tyr-Gtir ' Glu-Leu-Ata-Arg-Laj-D-CLn * MH2; (M «2i〇-Phe-V * l * Pp〇-ite * Wie-Thr'Tyr-Cly-Glu-Leu '^ la-Ari- Lcu-0-Cln-MH2i (K «3N +)-Ph * -V» L-Pr〇-nt-Phe'Thr-Tyr-CLy-GlU'Leu * Ali-Arg-Leij-D-Ctn-KH2; ( JI-KeJ-Rhe'ViL'At · *! L ** Phe-Thr-Tyr; Gly + CLu-Leu'Ala * ArB-Leu-D-Gln-liH2; (Ke2M) -Ph «-V * l- Alt-U * 'Ph «-Thr'TYr-Gly'Giu-L * u-Atft-Arg-Leo-0-Gln-MH2; (M * 3H + ^ Phe-V» l * Al ** Ut * Phe * Thr-Tyr-Cly-Glu-Leij-Ale-Arg-LeyO- &lt; * tn * iiH2 # and their peony acceptable addition salt. The compound of the invention is selected from the best specific examples, this ^ (Please read the notes on the back, please fill in this page) I · 30 _'j Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (M'K « ) &quot; Ph * -V * t-Pro-1 tt-Phe'Thr-Tyr'Cly'CttcLeu-Gtn-O-Arg-Leii'Cln-OH; (M «3H +) '^ e &quot; v * t * Pro-He'Phe-Thr-Tyr'Gty-Glu-LetJ'Ctn-0 * Ara * L «J-Gtn-HH2; Oi'MO-Phe-yit ^ Ati-I te-Mi« -Tfir-Tyr- Cly * Gtu-LwJ * Gtn-0-Arg-Ceu-Gtn- »iH2; (M-Hi) -Pht-V» t-Pro-JU-Ph «-Thr-Tyr * Gly-Glu-Leu'Gln- 0-Arg * leij-D-Gtn-iiH2; C «-M«)-Ph * -V * t * AU-I t * -Wie-Thr'Tyr-Cty'CtU'teij-Gtn * 0 * Ar9- Leij-Ly »-MK2; (Me3M +)-Ph« -V * L-At * -IU'iPhe-ThP-Tyr-Cly-Clu-Leu-Cln-0-Ara-Leu-Lv * -KH2;-2 8 * This paper size is in accordance with Chinese National Standard (CMS) A4 (210X297 mm) 134261 A7 B7 λ Printed by Masonry Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs 5. Description of Invention (26 (W'HeJ-Hie-Vel'Pro 'I te-Ph «-Thr-Tyr, -Cly-Glu-teu» GLrrD * Ar5-Ltu-Lys-MH2;-Pro-1 ti-Phe-Thr-Tyr-CLy-Glu-Leu-Cln-O- Ari- Leg-Ly * -MH2; (Me3 &gt; i *)-Wie-V * l'Pro-l l * -Phe-Thr * Tyr-Cly-Giu-L * u- GlnTD-Arg * Leu-Lyi * MH2; &lt; M-Me) -Phe-VtL-? Ro-l te-Wl * -Thr'Tyr-Cty-Glu-Leu-Ala-0-Ar5-Leu-Ctn ' KH2; (H «3H +)-Ph * -Vtl * Pro-1 t * -Pti * 'Thr', TyrfcG ty'-Gtu-Leu-At ** 0-Arg-Lfrij'CLrt-MH2; &lt; WH« ) -Ph «-V * t-Pro-I l * -Phe-Thr-Tyr-Gty-Glu-Leu-Ala-0 * Arg'Leu-0-ClrrHH2; (WH * i-W &gt; eV» t- Ala-nt-Phe * Thr-Tyr ~ Cly-Glii * Leu * Ala-0-Arg-Lftu-Lyi-ltH2; (^ 2 * () ί '^ * ^ ν * 1 * ΑΙ · -Π * -Ρ ^ ** ΤΗΓ-Τντ-εΐγ-01υ-1 »υ * ΑΙ * -0-ΑΓΑ * ίίυ-ίν» -ΚΗ2; It-Phdhr-Tyr-GlyGlu ^ Leu-AltD-Arg-Leu-Lyi-KHs; ro -1 l * -Phe * Thr-Tyr * Cly-ClLi-Leu-Ala-0-Arg-ley'lyt-KH2; (H «2 *) _ Pti * _V» l_Pro-I le-Phe-Thr-Tyr- Gly + GlLhLeu-Ale.D-Arfl-Lwj-kyi-MHs; &lt; H * 3) i +)-Wi * 'Vil * Pro-i le-Ph «-Thr'Tyr-Cly-Clu-L * uA [ »-D * Arg-LtiJ-lyt-MH2; (N * M) -Wii-Vit-Ali-Ilt-Wi * -Thr ^ Tyr-Gly-Clu-» L * u-AU-0-Ape-Lt &lt; j-0-Ly »-IIH2; {HtjM ^ J-Pht-VeWAU-llt ^ Ptw-Thr-Tyr-Cly'Ctu-Leij-Ala-D-Ara ^ leu-D-iyt-iiHj; t * -Phe -Thr-Tyr-Gly-Gtu-Leu-Ala * 〇-ArB'Leu-D-iy ** llH2; (H-Hc) -Phe * Val, Pro-Ile-Phe, Thr-Tyr.Gly-Glu- Lfta'G] n-Ar9, L «j_Lys.MHj, (MejN ^- Phe'Val-Pro-ne'Phe-Thr-Tyr-Sly-Glu-Leu-filn-D-Arg-Leii'D-Gln-NHj: and its excipient-acceptable addition salt. (Please read the notes on the back and fill in this page.) We can use this method or borrow the classical phase method to use polypropylene-based, Kieselgithr group molecules to grow benzylacetamido or hydroxymethyl benzyl hydrogen, Trifluoroacetic acid is prepared by different methods of peptide chain by acid hydrolysis. Sequentially build yhipe.) Ϊ Use appropriate solution to the resin, '4-methyl (Η Μ PA) 〆 部 fluoromethanesulfonate to the solution of resin branch technology. Phase synthetic resin support polysea complex (P0 1 synthetic resin. Peptide chain fixed methyl (PAM), oxyethoxy (TFA), tri-linked by the linker method, such as by the present invention Allosteric peptide chain, canonical or polypropylene: ·! 'S susceptible acid-breaking support, benzhydrylamine moieties. The solid-phase peptide synthesis can then be excised from the acid (TFMSA) holder. In solid form Is the use of amine / bad link 乇. Such as hydroxymethyl (MBHA), through the use of fluorinated and the like. 29- This paper size applies Chinese national standards (CNS &gt; A4 rules (210X297 mm) V. Description of the invention (27) A7 B7 Acetic acid SS TT- Linamine intestine The method is compatible with the solution or the base phase, and the solid peptide K is mostly inactive. It is printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs or printed by the peptide chain fragment. The carboxyl moiety of the carboxyl group reacts with another appropriately protected amino group or peptide chain fragment K to form a new hydrazone. To perform the coupling reaction, the hydrazine moiety needs to be activated. Activation requires the use of a standard coupler. Mixtures such as DCC, DIC, EDCC-BOP, HBTU, or PyBrOP are completed. In addition to PyBrOP, Mohr's HOBtM can be added to inhibit the racemization of the activated amino acid component. When the carboxylic acid corresponding to the amino acid is required, In the case of salt M activation, bases such as NMM, DIEA, or TEA can be used. On the other hand, the polypeptides of the present invention can be synthesized by coupling with activated esters K that make up the amino acids. Such activated esters include, for example, Wumo Phenyl esters, pentafluorophenyl esters, p-nitrophenyl esters, and the like .: When preparing the peptides of the present invention, it is necessary to protect the other reactive functional groups of the amino acid precursor with a suitable p-protecting group. .Usually ... 《-Amine Protection Basic Decision The type of branching protecting group that must be used. For example | In the case of protecting an α-amino group to its Boc derivative, benzyl alcohol esters, ethers or urethane derivatives are usually used to complete the protection. Some have been successful with esters and ether derivatives of cyclohexanol. Conversely, when the α-amino group is protected as its Fmoc derivative, the branched functional group is usually protected as the tertiary-butanol ester, ether or Amines are ethyl formate derivatives. Of course, the protective groups can be changed to each other, especially when the peptides of the present invention are synthesized by the lysate phase method. Removal of the Fmoccx-amino protecting group can be easily accomplished, typically pyridine. Treated with TFA in the presence of an appropriate carbon ium scavenger can remove the branched-chain protective group, and can cut off the C-terminal and tree gift of -30. This paper is applicable to the national standard of t country (CNS) A4 specifications (210X297 male |) I ------: — r equipment— (Please read the notes on the back and fill in this page) Ding 6 434) 261 ^ A7 _B7_ V. Description of the invention (28) •. · 'Link between links. Boc protecting groups are usually removed by dilute TFA treatment. However, after the KTFA is cleaved, the α-amino group will exist in the form of its TFA salt. In order for the α-amino group of the growing peptide chain to react with the next amino acid derivative, it is necessary to neutralize the resin-bound peptide with a base such as TPA or DIEA. Then, a strong acid such as hydrogen acid or TF MS A containing an appropriate scavenger is used to protect the amino acid branch and cut the peptide chain from the resin support. According to the present invention, we provide a method K for preparing a peptide containing an amine-terminal moiety (R:) «(R2) (R3) N-. When B = 〇, 1 {2 is hydrogen or lower alkyl and R 3 is lower-carbon alkyl, this method involves making N, as appropriate, bound to a suitably protected peptide via an appropriate linker on an insoluble support -The terminal amine group (HLOUA) /) is reacted with an appropriate aldehyde or feed and an alkali metal hydrazone cyclogen. The aldehyde or _ may be, for example, formaldehyde, acetaldehyde, or acetone. The rhenium metal hydride may be, for example, an alkali metal borohydride such as sodium fluoroborohydride. This method is usually carried out in a suitable solvent at normal temperature, such as DMF-, or NMP, and optionally with acetic acid or 1-hydroxyethylpyrrolethanesulfonic acid (HEPES). This method is described in US Patent No. 4, 42 1, A more complete description is provided in 744, and its disclosure is also listed in K herein for reference. Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs (please read β on the back of the page and fill in this page) when m = l *! ^ And 113 are independent low-carbon fluorenyl groups or dipropyl groups, and fluorene 2 is only Can be selected from lower alkyl, allyl, and propargyl groups. This method involves making the L-terminal N-terminal amine group of a properly protected peptide bound to an unsupportable via a suitable linker ( NR2R3-(A) on) is reacted with a representative compound, wherein L is as defined above and h / i is a halogen atom. The reaction is carried out in a suitable solvent such as DMF or HMP in the presence of an acid-binding agent such as sodium carbonate or potassium carbonate. The method is in Benoiton-Chen, -31-This paper size applies the Chinese National Standard (CNS) A4 specification (2! 0X297 mm) 434261 * A7 _B7__ V. Description of the invention (29) P r 〇ced. 1 4 th · R ur ο p. P adt. Symp.. (1976) is more clearly explained on page 149, the disclosure of which is hereby incorporated by reference. Since the compound of the present invention is effective in the form of a free base, is it acceptable to formulate and apply the acid-addition salt of Krypton to stabilize and facilitate crystallization and increase? ^ Resolution or similar purpose. Acid addition salts are traditional methods made from organic or non-acetic acid forms such as hydrochloric acid, sulfuric acid, sulfonic acid, tartaric acid, fumaric acid, hydroacids, acetic acid, citric acid, malic acid, phosphoric acid, succinic acid, acetic acid , Nitric acid, benzoic acid, ascorbic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, -propionic acid, and the like. The acid addition salt M is preferably made of hydrochloric acid, acetic acid or succinic acid. The compounds of the present invention can be combined with a drug-acceptable carrier to provide a pharmaceutical composition. Suitable carriers for the free base of this compound include glycerol-water, isotonic water, sterile water for injection (USP), emUlphorTM-alcohol-water, cremophor-ELTM, or other suitable compounds known to those skilled in the art Carrier. Carriers suitable for acid addition salts of the compounds of this invention include isotonic water alone, sterile water for injection (USPT, or in combination with other dissolving agents such as ethanol, propylene glycol or others known to those skilled in the art; traditional dissolving agents). One of the preferred carriers is the isotonic aqueous solution of the compound of the present invention. _ Employees of the Central Standards Bureau of the Ministry of Economic Affairs. Consumer cooperatives Yinfan (please read the notes on the back and fill in this page). You can use an effective amount of the present invention. Activating activity of diarrhea in mammals, such as animals or humans, is required. Since the activity of the compound varies with the degree of therapeutic effect required, the dosage of the compound used is also different. The exact dosage administered will also be It is determined by factors such as the individual sensitivity of the patient's physical child and the specific patient. Therefore, the unit for the specific patient (man) is excluded. The paper size applies the Chinese National Standard (CMS) A4 specification (210X297 mm). ) 4342§i A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (3Q)-. ♦ * The difference in dosage can start from 0.1 μg / kg body weight Set to the desired effect. The preferred minimum dose for titration is 1 microgram / kg body weight. Unknown compounds can be administered using the well-known parenteral route κ sterile solution or suspension and the previously described carriers. These preparations It should contain at least 0 ^ 1 *: the weight of the compound of the present invention, but the difference in this amount can be from about 0.12 to about 50¾ (the weight ratio of the compound of the present invention). The compound M of the present invention is preferably administered intravenously and used The dosage is usually from about 0.1 microgram to about 500 mg / kg body weight and M is preferably from about 1 microgram to about 50 g / 70 kg body weight. The dosage can be administered 4 times per day. The sterile solution used Or suspensions may also include the following adjuvants: sterile diluents such as water for injection, saline, non-volatile oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or hydroxybenzoic acid Methyl esters, antioxidants such as ascorbic acid or sodium metabisulfite, chelating agents such as ethylenediaminetetraacetic acid (EBTA), yuan granules such as acetate, citrate, or diacetate and tonicity adjustment , Such as sodium chloride or glucose. Parenteral preparations can be filled in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. I have referred to different reports when applying the present invention. In order to explain the situation of the technique in more detail, the disclosures of these reports are also listed here for reference 2-. I will further illustrate the present invention with the following examples, but the purpose is only to show, not to limit the compound of the present invention. Example 1. [12-D-Spermine, 13-Leucine] Kitchen Motilin- (1-14) -Peptide (pig) Di-trifluoroacetate-33- This paper is suitable for paper China National Standard (CNS) A4 Specification (21〇 &lt; 297 mm) (Please read the precautions on the back before filling this page) '. 装 _

I order

-AW Printed by the Central Standards Bureau of the Ministry of Economy—Industrial and Consumer Cooperatives 434211 A7 __E __- V. Description of Invention (31) ''-. · «H-Phe-Val-Pro-He-Phe-Thr-Tyr-Gly-Glu- Leu-GIn-D-Arg-Lcu-Gln-OH. The peptide was MillfGen Model 9050 peptide synthesizer with solid-state coupling / kinetic technology at 2.0 grams of Fraoc-L-Gln (Mbh) PepSyn KA resin (0.097 milli-equivalent / G.) On synthesis. Except that .Thr is the ODhbt ester, all the residues used are coupled to the Pf p ester of Fmoc amino acid under the condition of HOBt. Branches are protected as follows: D-Arg (M-tr), Glu (OtBu), Tyr (tBu), and Thr (t Bu &gt;. GU is unprotected. Use Fmoc amine with more than 4 moles for coupling The basic acid 0Pfp / H0Bt was performed in DMF. The coupling rose rate was determined by Kaiser test. The coupling time was 4 hours. After each coupling period, K was dissolved in 20¾ pyridine of DMF to remove the Pmoc-ct-amino acid protecting group. Synthesis Then the resin-bound peptide was washed with DC M and dried overnight under vacuum. The resin was used to block and cut the fluorene chain. It was at room temperature 1000 M anhydrous TFA containing 3% sulfotoluene and 3¾ ethylenedithiol and 2¾Toluene (total 20 ml) was shaken for 8 hours. Then the cut solution was added dropwise to 250 ml of cold ether and the precipitated peptide was collected by filtration to obtain 320 mg (8 5 3J) of the title peptide as a white powder. ). Pure makeup is made of ία C in Waiters De 11a-Prep 3 0 0 0 using two flail C-18 columns (250 20 mm, 15 microns, Vydac for three rounds (typical load factor = 107½g / round). The solvent system is OU TFA with a 30 minute gradient to 6'0 $ gas methane / 40¾ TFA (0.1¾) at a rate of 20 奄 L / min, and is subjected to UV 22 (ίnm detection. Purity of individual fractions by K analytical HPLC (30 minute gradient, 100¾ TFA (0.U) to 100¾fluoromethane-, 1ml / min, 214nm, = 17,37min) -34- This paper size applies to China, China Standard (CNS) A4 specification (210X297 tolerance) (锖 Please read the weeping matter on the back before filling in the poverty), and install it.

I order 434261 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (32): &gt;. * · And capillarity thunderstroke evaluation. The pure fraction was collected (&gt; 95 丨) and freeze-dried K to provide 107 mg (28¾) of the title polypeptide as a white hair powder. AAA: Thr 0.δ7 (Γ), Glx 3.02 (3), Gly 1.04 (1).

Val input 1.02 (1), lie 0,92 (1), Leu 2.14 (2), Tyr 1.00 (1), Phe 1.9.3 (2), Arg 0,93 (1), FAB-HS: (H + H) + Calculated value 1 7 1 2 and found 1 to 12. -Example 2 [N-methylphenylalanine, 3-alanine, 1-alanine, 12-D-arginine, 13-leucine, 14-D-heteroamine] Periodin-(1 -14) -peptidylamine (pig) h is-trifluoroacetate (N-Me) -Phe-Val-AIa-Be-Phe-Thr-Tyr-GIy-Glu-Leu-X] aD-Arg-Leu -D-Lys-NH2 · t .. The peptide was synthesized on a 0.85 g PAL resin (0.27 meq / g) using a Mill (ien. Hodel 9050 peptide synthesizer by solid phase continuous flow technology. The resin was mixed>乂 3.4 grams of glass beads (pickled, 150 卩 212 microns) 'Dry Fill 1'; into a continuous flow column and swell K DMF for 1 hour before use. Borrow flowers._ 0.6 Molar concentration in DMF j Under the conditions, MBOP and HOBt couple with Fmoc-MePhe-〇H (1: 1: 1 >>. '. Fnioc-L-Thr-OH with its ODHbt is cooler than with HOBt. All other / residues are in H. Coupling with Pfp ester of F »oc amino acid under Bt conditions. The branching protection groups are as follows: D-Arg (Mtr)% GIu (OtBu), Tyr (tBu), Thr (tBu), -35- This paper size applies China National Standard (CNS) A4 specification (210 &gt; &lt; 297 mm &gt; ------------ c. Equipment -------- ΐτ ------ Q --- ----- ^ —-—-(Please read the note on the back Please fill in this page for further information) Μ &quot;-A7 B7 Printed by the Central Government of the Ministry of Economic Affairs of the People's Republic of China, the Consumers' Cooperatives Co., Ltd. V. Invention Description (33) .. · D-Lys (Boc), Gln (Trt). Fmoc amino acid derivatives with more than 4 moles in DMF. The coupling efficiency is detected by KaiSe's test. The coupling time is typically 4 hours. After each cycle, M is dissolved in 20M pyridine to remove Fmoc- ot-amino group. Protective group. After synthesis, wash with DCM and bind to the resin with DCM and dry overnight under vacuum. At room temperature, use anhydrous TFA containing 5¾ sulfurized toluene ether, 3SI ethylene disulfide and 2¾ toluene ether ( 20 ml in total) Shake for 8 hours to block and cut the peptide white resin. Then add the cut solution dropwise to 250 ml of cold ether and collect the precipitated peptide by filtration to obtain 210 mg of the title peptide as a white powder. (91¾). Two consecutive L-18 columns (250 X 20 mm, 15 micron Vydac) were used for three rounds (typical load rate = 70 mg / round) in Waters Delta-Prep 3000 by HPLC to purify the peptide. Solvent system 0.1¾ TFA 30 minute gradient to 60¾cyanoethane / 40¾ TFA (OU) at a rate of 20 Liters / min, and detected by UV 220 microns suddenly. The purity of individual fractions was evaluated by analytical HP LC (30-minute gradient, 100¾ TFA (0.15;) ^ 100¾fluoromethane, 1 ml / f min, 214 nm, Rt = 17.06 min) and bale electrophoresis. The pure fraction was collected (&gt; 95%) and freeze-dried to provide 82 mg (36X) of the title polypeptide as a hairy white powder. •., I AAA: Thr 0.95 (1), GΓχ 1.04 (1), Gly 1.04 (1), ~ Val 0.74 (1). Lie 0.99 (1), Leu 2.11 (2), Tyr 1.01 (1), Phe 1.01 (1), Lys 1.03 (1), Arg 1.05 (1). FAB-MS: (M + H) t calculated 1641 and found 1641. -36- This paper rule applies to Chinese National Standard (CNS) A4iMS · (210X297mm) (please read the notes on the back and fill in this page again), 'Binding 4 342 &amp; 1 A7 B7 V. Description of the invention (34) Example 3 Dimethyalamic acid, 13-leucine acid] Jiakinin-(1-14) -peptidylamine (pig) bis-trifluoroacetate (l ^ N) -Phe-Val-Pro-Ile- Phe-Thr-Tyr-Gly-Glu-Leu-GIn-Arg-Leu-Gln-NH2. The solid phase continuous flow technology was used to synthesize this polyimide on a HovaSynPR 500 resin using MilliGen Model 9050 peptide synthesizer K0.2 millimolar scale. shape. Except for 1 ′ {^ _ is 00111) 1: ester, all residues are Pfp esters of MFAoc amino acids, which are coupled under HOBt. The branching protection groups are as follows: Ars (Mtr), GU (Trt), GU (OUu), Tyr (tBu), and Thr (tBu): When coupling, use Frooc amino acid with more than 4 moles dissolved in DMF OPb / HOBt. Coupling efficiency Κ ί a i se r * Test detection. The coupling time is 4 hours. After each coupling cycle, M was dissolved in 203K pyridine in DMF to remove the Fmoc-ot-amine protecting group. After synthesis, the resin-bound peptide was washed with M DCM and dried under vacuum overnight. The resin containing the fully compatible peptide was then transferred to a 20 ml HMP bottle. 5 ml of 37¾ formaldehyde solution (300 equivalents), 126 mg of sodium cyanoborohydride (10 equivalents), and ho microliters of glacial acetic acid were added to the suspension. Read the precautions on the back before filling out this page). The mixture was stirred for 7 hours. The resin was filtered and washed with M DMF (5 50 mL) 'DCM (5 x 50 mL) and dried under vacuum. Anhydrous T ^ A 3¾ ethylene dithiol and 2¾ toluene ether (total 20 ml) containing 5¾ sulfotoluene at room temperature were shaken for 8 hours. K The peptide i resin was blocked and cut off. The cut solution was then added dropwise to 250 ml of cold ether in humans and the satin peptides were collected to obtain the title peptide as a white powder. By HPLC in _ 3 7-This paper size is applicable to China National Standard (CNS) A4 (2I0X297 mm)

4342SI Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of Invention (35) ''

Waters Delta-Prep 3000 uses two flail C-18 columns (250 X 20 mm, 15 μm Vydac) for 3 rounds (typical load rate = 70 mg / round) to purify the peptide. The solvent system was O.U TFA with a 30-minute gradient to 60¾cyanoethane / 40¾ fFA (0.U) rate of 20 ml / min. And was detected at 220 nm. The purity fraction (&gt;Q53;) was collected and lyophilized to provide 111 mg of the title polypeptide as a fluffy white powder. AAA: Thr 0.84 (1), Glx 2.88 (3), Pro 1.03 (1)

Gly 1,04 (1), Val 0.47 (1), lie 0.87 (1), Leu 1.88 (2), Tyr 0.90 (1), Phe 0.97 (1), Ars 0.86 (1). FAB-MS: (M + The calculated value of H is 1 738, and the result is 1738. Example 4 ^ [1-NU-trimethylbenzylanine, lh leucine] Actin- (1-14) -peptide (pig) bis- Trifluoroacetate (Me3N +)-Phe-Val-Pro-IIe-Phe-Thr-Tyr-Gly-GIu-Leu-Gln-Arg-Leu-GIn-OH. Hi MilliGen Model 9050 peptide using solid phase continuous flow technology The peptide was synthesized on a FMOC-1 (GlndMbh) PepSynKA resin on a 0.2 millimolar scale. With the exception of Thr (fDhbt ester), all residues are in the Pfp 醏 form of M Fmoc amino acid and are coupled under HOB /. The branched chain protecting groups are as follows: Ars (Mtr), Gln (Trt), -Giu (〇tBu), Tyr (tBu) and Thr (tBu). When coupling, use more than 4 times the mole number of -3δ- This leaflet scale is applicable to China National Standard (CNS) Α4 size (210X297 mm) (please first Read the notes on the back and fill out this page.) Order 434201 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (36). »'

Fmoc amino acid OPfp / HOBt. Coupling efficiency M Kaise "test detection. The coupling time is 4 hours. After each coupling cycle K is dissolved in 20¾ pyridine of DMF to remove the Fmoc-ct-amine protecting group. After synthesis, the peptide bound to the resin is washed with DCM and Dry overnight under vacuum. Then transfer the resin containing the perfect peptide ^ 20 ml Η MP flask. 5 ml of methyl iodide (40 equivalent) was added to this 懋 float, followed by 500 milligrams. G Potassium carbonate (18 equivalents) was stirred for 12 hours. The resin was filtered and washed with M DHF (5 X 50 ml), water (2 X 25 ml), DMF (5 X 50 ml) and dried in vacuo. At room temperature -M anhydrous TPA containing 5¾ sulfotoluene and 3¾ ethylene disulfide and 2! S methylbenzyl ether (total 20 ml). Shake for 8 hours to block and cut the peptide chain from the resin. Then cut the solution Add 250 ml of cold diethyl ether dropwise and collect the precipitated tritium through tritium to obtain the title polypeptide as a white powder :. Two Flax C-18 columns (250 X 20 milliamps, 15 micron Vydac) for 3 rounds (typical load rate = 70 mg / round) to passivate the peptide. The solvent system is 0. 1: ¾ TF A 3 0 minute gradient to 60% methane / 40 ¾ TF A (0.11) at a rate of 20 ml / min and detected by UV 220 nm. The pure part of the total collection 095 ¾) and freeze-dried M Provides multiple titles of hairy white powder (: makeup 7 1 mg. AAA: Thr 0.88 (1), Glx 3.25 (3), Pro 1.00 (1)

Gly 1.00 (1), Val 0.30 .. (1), lie 1.01 (1), Leu 2.30 (2), Tyr 1,10 (1), Phe 1.10 (1), Arg 1.10 (1). FAB-MS: (M + H) Calculated 1753 and found 1753. -39- This paper Λ degree is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back of this page before filling in this page)

1T ip 4Ι34) 2δ1Γ Α7 Β7 V. Description of the invention (37) · * * Example 5 M 2¾ pig kidney tincture homogenate was subjected to in vitro spike qualitative tests like most small linear peptides. It is believed that motilin is produced by the kidney. Brush border cell metabolism. Therefore, we chose the kidney homogenate as the model system for evaluating the relative biological spike in the peptide of the present invention. All are to be researched. All are kept in a 25 保温 〇 pig kidney (Pel Freeze, Inc.,

Rogers, Arkansas) ¢ 2¾ weight / volume, terminal pulp volume = 4 liters; buffer solution = HEPES & &gt; Η 7.0). Both the initial substrate concentration and the Fmoc-Gly concentration were 0.5 mg / ml. In order to determine the appropriate incubation time and sampling interval, the propylene experiments were performed on each peptide. The first round was used as an initial assessment of peptide characterization. All samples were double-replicated. The sample volume was 180 microliters. ; Purify the sample by adding 20 microliters of 100 $ TCA (final volume = 200 microliters, final TCA concentration = 1 &lt; η). Equilibrium, 5-10 seconds to determine the equilibrium, and then centrifuge to remove the precipitated protein. Analysis was performed on a Waters HPLC system equipped with a WIS P autoinjector, a 5 micron Vydac C-18 analysis column, and a Waters 4S1 (JV detector set at 214 nm. The initial solvent conditions were 80 ¾ gas methane / 20 ¾ ( 0. '%) TFAM dissolved in Mil 1 iQ water runs to 63¾ 氤 methane / 37¾ (0.1%) TFA in 35 minutes. The rate is 1 ml / min. 4 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( Please read the notes on the back of the history and then fill in the tile.) The peptide substrate and metabolite peaks are proportional to the internal standard and the ratio of the duplicate samples is averaged. It is assumed that when processing data, it is a first-order kinetic type. The rate of mass loss is using the Enzfitter formula (Biosoft) | ten calculations. Relative half-life -40- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 (Public *) Printed by A7 __B7_ of the Central Standards Bureau of the Ministry of Economic Affairs. __B7_ V. Description of Invention (38), * * The period is determined by the following relationship: ti / 2 = 0.693 / k &gt; Example 6 Throbbing. Body binding affinity determines the stomach of the peptides of the invention Receptor binding affinity is determined by the general method of Bor raans, Peeters and Vantrappen, Regu 1. P ep t., 15, 14 3-15 3 (1986). This peptide is substituted for rabbit stomach treasure The ability of [12SI-Tyr · 'Hie13] actin (pig) of smooth muscle cell membrane is determined by repeated testing of M Mol concentration twice each time. To determine the concentration to replace the 50¾ calibration substance (ICBO), the calibration is assumed. It has the same affinity with the unlabeled motilin and single-type chitin as a non-cooperative person, and it is obtained by describing the information g instead of the equation. I use SAS-package software ( SAS Institute, Inc., Cary, NC, USA) Iterative least-squares procedure was performed. From a large series of control experiments, we calculated that the dissociation constant of motilin itself was 0.7 5 nanomolar Concentration (pKd = 9.12) ^, and use this value in all calculations. Instead of the concentration of 50¾ calibration standard μ its negative ^ value (pic ε〇) I. _ ... Selling Example 7 rabbit duodenal smooth muscle fi Tissue bath analysis of the M-segment shrinkage response in the duodenum of rabbits According to Depoo "tere et al." J. Gastrointestinal Motility, 1, 150-159 (1989) -41- This paper size uses the Chinese National Standard (CNS) A4 specification (210X297 mm) I ------- o Pack-(Please read the notes on the back before filling this page)

-Q 434aif A7 B7 V. Description of the invention (39) The steps printed by the Consumers' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs will be decided in the bath waiting for Zhang Jie. The experimental steps include an equilibrium time of 1 hour, a cumulative dose-response curve of a compound of 10-7 moles of motilin, followed by a wash-out period followed by a challenge of 10-4 moles of acetic acid, and finally Ethylcholine of ι〇_4 moles. If the difference in the final response to ethyl molybdenum at 10.4 moles ^ is greater than the initial response by more than 5¾, this result is discarded. The compound was tested at 10Γ 11-10-4. Molar concentration. Corresponds to the highest response to motilin (Eudsos: This point is determined by the data point in conjunction with the equation E = E »ex (l + ECB〇 / [L]). For weakly effective compounds, we use the right -ΙΟ— 7 The 90X response of Molemato motilin is referred to as E «βχ. The dose that produces 50¾ is expressed as the negative logarithm (pEC50). Example 8 Contractile activity in the gastrointestinal tract of dogs: ^ Gobabitur 6.5 mg / kg intravenously for mixed-sex dogs of both sexes (Hi. Anesthesia. Midline incision in the abdomen. Locate the duodenal segment, identify the distal artery at the end of the segment, and identify the closest possible artery of appropriate size Remove the fat and tendons. Bend an appropriate diameter needle at an angle and insert the needle tip into the cleared artery. Position the needle in the artery for about 30 seconds until the vasospasm relaxes, then insert the catheter assembly into the artery and M: 0 00 silk suture ligation and positioning. Cut the thin polyethylene catheter at one point on the other end and insert the __ and the needle at the other end. Insert the center of the needle into a 3-channel adjusting bolt &gt; Heparinized glucose M Burlinger bicarbonate Fill the catheter combination. Inject Krieber's pellets (excluding air into the arterial catheter and record the bleach distribution of the artery. If the area is too large, the artery on the same side can be ligated as long as the circulation in this area is maintained. Then stitch the Bass type linear valve to the pulp 42- This paper size is applicable to the national standard (CNS) A4 size (210X297 mm) (please read the precautions on the back before filling this page), and install. _ 一 Order 5 2. Description of the invention (4〇Α7 Β7 The film is printed and oriented by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, so the ring-shaped muscle contraction can be recorded on the Beckman R611 power chart instrument. The silver wire electrode is inserted into one of the serous membranes of the linear valve. The stimulus separation unit is connected to the Grass S88 electrical stimulator. The applied electric field stimulation is 40V 0.5ras and 5 ρρ &lt; and the amplitude of the pen recorder is set. The ant contains contraction anti 堀 Γ 0 All peptides to be injected are dissolved The Kleiber fluid was diluted in parallel so that the maximum concentration for any injection was 1 ml. Except the Kleiber stock solution, all solutions were placed on ice on the day of the experiment and discarded at the end of the day. Curve · At this location, first a bolus of heparinized Kreb's solution in a volume of about 1 ml was injected to provide a rapid control. The peptide antagonist was injected in a logarithmic increase (1 ml volume was injected into 1 ml Cree). Solution until the highest amplitude is available. Then, Kripper solution containing OU BSA is flushed to replace any peptide remaining in the arterial line. For peptides used for motilin receptors, care must be taken Do not inject more than the maximum dose, as it will cause a rapid rabbit disease response. Therefore, when the response begins to be obvious, use an increase of 0.3 or 0.5. Logarithmic units. Use M to determine the dose response. The position can only be every 1/2- Use it for 1 hour. Measure the corrective response radiance of a wide range (f i e 1 d) stimulus at each position and make it 100 ¾ of that position. Determine the response radiation to each dose of the antagonist I. Calculate the S! Relative to the calibration curve and plot the concentration. The response EDs0 represents the amount of antagonist required to produce a response of 5.0 ¾ '. It reflects the efficiency of the reaction and the efficacy is 2%, but the two cannot be discriminated. 43 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 &gt; α 97 mm). Please read the precautions before reading Λ before 434211 A7 B7 V. Description of the invention (4 Table 1 1 Effect of motilin receptor antagonists on binding and contraction experiments Compound PEC5Q pIC5〇EL * u133fi «T〇-2rj printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 8.13 9.15 a (* u, 33pwrci-u) 7.55 0.3d EP-Arj32, t * u133pMOTiVH ^ Uk 9.01 ®-Αγβ12, L * u13Jf «QTC1-H) 7-50 β · Μ CM · 3, Proamine 7,74, β · η CD'Ari12, Hu13, Ly »u3fi« T (VU) 7-13 β.59 CD-〇m12 * L * u13! fH0T〇-U} ~ 6.8.3 P'Gln12, L * ul3] p « T (1-H) t 7.06 ».25 [D'AU12, L # 〇13Jf« TCM;) 7.29 8,05 {D * Arfl12 (L * 〇T3JpWT (1-22) 7.67 8.7S tD ^ Ain12, ltu133F `` TC1-H) (6.S2 8.12 tPh * 7, D-Arg12 # L * u133fH〇TC1-H) 6,92 8.07 tD-AL * 8 # O-Arg12, L * u13Jf «TC1-H) 7-W 8.22 tCh * 1, D'Arg12, L «j13] pM3TC1-U) 7.60 8,75 f1 [Air *, O-Arg12, L * u15] F # eT (lH) 7.71 Β · £ 7 OU · 11, D-APt12 # l * ul3] p # T (1-U) 7,43 * la ^ (At · 11, D-Arg1 ^^ Leu ^ iDHyi ^ J ^ HOTiVU) 7.B0 9.35 P-Qw 'Mi ?, Al / 1 · Ο-Αγβ1' L * u13iD-Ly * 143pw〇TM.14} tenamine 7.25 9.03 OMUrti ^. D-Arfl12 · L «u13. Ly» UJF «Tn-1〇vine 7-7 * 9.10 This paper size applies to Chinese national standard ( CNS) 8 specifications (2I0X297 mm) 4342®1 A7 B7 V. Description of the invention (42 Table 1 (M on the previous page) &gt; Effect of telokin receptor antagonists on binding and contraction experiments Staff of Central Standards Bureau, Ministry of Economic Affairs Consumer cooperation Du printed compounds., P £ Cs〇pICS〇Ltu13, Lyi1 * Ip «T (1-14 &gt; Phenylamine 7.74 9.3Z W-Hcfh * 1, At» 11, D-Arg1z (Leu13, Lyiulp «T 〇-tA) .e.oi 9.33 W-MtPh * 1, LW13, ratamine 7M 9,21 0-Arg1Zf 〇-Gln14] p «〇ril-U) basic amine 7.77 9,07 W-Mifh * 1, Al · 11, D-Arg12, L «j13_ D-Gln14】 F # M3TCl-14) Selamine 7.97 ♦ 9.07 D ^^ Ph * 1, teu13, 0-Ctnu] pWT &lt; M4) 7.W a.7i • Ktl CH «3H + Phe1 (D-Αγη12, Ltu13, D-ClnUJp« T (1-U) 7.39 B.71 AU11, D-Arp2, Leu13, D-Glf &gt; U] p «OT (114) Proamine '' 7.25 SM W-HtPh * 1 · AlP, L * u13, Ly »14] p« 〇nM4 &gt; Tetanamine 7.7Z 9.21 [K- &gt; W &gt; h · 1, D-Αγβ12, L * u13) pWTCl-H) 7.71 8.72 W * j «* Phe1, AU3, Ltu13. Ly * 14】 pH0T (1-U) hydrazine '' 丨 7- 58 2.52 D-Αγβ12, L * ul3: f «OTCl * 14) 7-52 S, 45 Al» 3, D-Ary12, L * u13, Ly »U: f« T (VH} 7 * 72 9.20 O ^ JM + Ph · 1, Al · 3, 〇-ArV2 · Uu13, LytApKiTO-Uf blocked 7_32 8 * 72 a-ikftit1, At · 3, 〇-Argia, L * u13, D-CtnU3pM〇T (VH) ^ gg 8.07 9 * 11 Al · 3 · &amp; -Ar · 12 · Ltu13 · D-dln143p «ni-lM 7-20 S.BS nH *» · 1 · Al · 3, 0. * rs12 · L » u1slt # eT (W43 Tengamine * 7.79 9.Ϊ3 Dtejlf **% · 1. Ail3, UulSlf «T (1.Ui Tengamine 7.i2 ¢ .79 (Read the notes on the back and fill in this page)

Private paper size applies Chinese National Standard (CNS) A4 (210X297 mm) Compounds printed by employees' cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. PEC5〇piC50 Α * 11, D_Arg12 · Uu131f «T〇.U) Amine 7.57 S .5fi 6-Art12, Iw13) f # 4〇TCVU) 7.95 8.99 D.Arg12, Leui3] p «0T (1-U) Ratamine 7.73 ΙΛ7 WM« i &gt; h · 1 · AU3 · Al / 'D-Αγβ12 , Leu13, Lyi14】 r &gt; «} Ul-U &gt; Ratamine 7.77 9.H We3M + Ph * T * AU3, AU '〇ΑΑ3131 ## Ι &gt; * υ13ΛγιΊ4] ρΚ〇Τ (1 · 14 &gt; saturated amine 7.59 a .72 tell · 5, B-Are12, L »u13】 pMT (1-u &gt; Phenylamine 7.30 a.17 〇 (· Η ^ · 1 · uJ33pii〇Ttvu) · * s 7.U e.5S W * 2MPh · 彳, ΐ · υ13] ρ «Τ (1 · 睦) amine, 7Λ8 8.57» &lt; 3 »+ 吒 八 Lw13] p« T £ 1-U &gt; 7.69 ΛΛ5 [EtzPIv * 1. L «u13 】 F * «U1-W) Amine 7.5A a." [K.li-OiHi-N-PropirgylPh * 1, Lkj13JF * WT (VH) '/ 7,6S a, 67 WJ ^ mropersytMrt1 · L * u13lp « TiVU) Ratchet 7.57 8-70 W * AUy Bu ", χ + OW ^ * 1, L * u13] p # WTiMM with amine 7Λ7 β * 76 At · 11, DA「 b \ Uu13】 p «T (1. U &gt; Styramine 7.60 9 * 03 W-MePh · ^ Mp, AU ^ (0-Ara ^ # Itu ^ pO-C lrx ^ lpMQTCl ^ U) ^ ¾¾ ^ 7-32 9.H ^ • Ϊ ^ Μι * 1 · AU3, Α ·· 11 · & H12 · LeJ ^ D-ClrOhpMOTd-U) ratamine 7.22 〇 (· Η * Μν · 1, Ale3 · AU11, D-Are12 · Uu13) pWT (1-U) Tetamine 7,63 9.33 L «J1 '| ^ 14: (* 01 &lt; 1-14) Tetamine 7.« S, 90 II : — Order ---------------- &gt;. Α7 Β7 V. Description of the invention (43) Table 1 (continued from previous page), binding and contraction of motilin receptor antagonists Effectiveness of spring inspection This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -----— L —------ il! R (Please read the precautions on the back before filling this page ) m42§t A7 B7 V. Description of the invention (44) Table 1 (缡 previous page) Effect of actin receptor antagonists on binding and contraction experiments Employees of the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Consumption Cooperation Printed Chemical Compounds, p £ C5〇picso AlP · At · "· D-ArijU · Stuffed amine 7,55 B, WW ^ Ph · 1 · AU11, D-Ars12 · Leu13, Lr» 14lf «T (1-U) Photo 7.64 a, 91 AU3, AL · 11, O'Arfl12, Leu13 # LyiKi ^ OT (1't4) IS® 7.74 9,15 'f * tr AU3, AL »U · 0 · ΑΓ312, Le ^ 3lFH0T (1-U) tenamine 7.31 B.71 β-ΑΓ912, Leu1 'Ly * 1'] pW3TtVt4 &gt; … 7,60 S, 93 CHtSW + Pt ^ 1, Μ · 11, D-Αγϊ12, L * u13, Ιγ * Κ] ρΗ0Τ〇 · Η) ratamine 7JA a.s9 [Me ^ Ph * 1, AU11, D -Αγβ12, tw13 (Day * U: pHOTCl-U) ^ ®t 7.69 a.54 W «2« Ph * 1F At · ^, Al · 11, D-Arg12, L * ui3,0-Lr * 14] p «0TC1-H) 7.73 a * 39 is called Sha yesterday /, &amp; · ΑΓΒ1Z · Leul3】 F« T (1-U) Fujinamine. T, 71 8,73 W ^ Ph · ', D-Ara1' L « I13, Lyi14] FH0T (1: 1〇 Tibetanamine 7.73 β_Ρ3 W «2« Ph »1, ΛΙ» 11, O-Ara1 ^ L »u13] p« T (M4J 7.76 β.Π 'PHOT Please read the notes on the back before filling out this page.) This paper size applies Chinese National Standard (CNS) A4 (210X297 mm). 5. Description of the invention (45) A7 B7. Table 2. Actin receptor antagonists at 235. Half-life in pig kidneys after homogenization Printed compound Tlfc a * u13lf «T (1-22) 30,2 aw ^ fWTci-H) r.3 tM'PUfh # 1, L * ul3] F «Tt1-U) 12.3 Ly» u] p «3Tii, ui Tengamine 20. CM-Htfh * 1, 0-Are12 # Ltu13lp« 0TCM4i J〇 • ^ 1 * »D'A「 812 · L * u13 · Ly »14】 f« JT (1-U) head amine il DC_3 + Ptt / · D-Ar ， 12 · ratamine D ， Ara1Z , Lev'hpWTd,] *) Tengamine 95 AU11, DA "i12 · i * u13, Ιν * Κ] ρ« ΤΠ · Η &gt; Film 34.3 AU11, D-Ar 丨 1Z, Lw1 'D, Gln14] F « T (1-U) Rattan V billion 6 AU11, D-Are12, L * uT3, D, Ly »u] f ^ 0T [1-14 &gt; Proamine 47 — Al * 11, D-Arfl12, Ltu13] p # ^ T (lU) Xueamine t3T.9 a-Ms ** · 1 · 0- * re12, L «U13 · Ly» uIfMTtV1 *) 醢 amine W [Κ- »· 3 *« ι · 1, / » · ". 0- * r» 12 · L «13, Lyi14】 p« T (1-U) amine 125 (please read the precautions on the back before filling in this page) The paper size applies to the Chinese National Standard (CNS) A4 specifications (210 &gt; &lt; 297 mm) 434a§1 A7 B7 V. Description of the invention (46) Table 3 Effect of motilin antagonists in the gastrointestinal tract of a dog Ministry of Economic Affairs t Central Standards Bureau Employee Consumption Cooperative Printed ED50 * a * ul3lF «T &lt; 1 * 22) 0.17 d.kj13ip« tci * U) Wi Uu13, Rattanamine 0.025 Οί-iUf ^ · 1, &amp; -Ara12 · L * u13, Triamine ΰ.025 Al · ” ， D-Ars12, L * u13, tyi14】 pWTtVU &gt; Rattanamine 0.3 · ΑΑθ, Ό.Αι12, L * u13, Ly * 14Jp «TilU) Rattanamine 0.06 bet 3 *» + »&gt; * 1, Ale3 · 0-ΑΓβ1Z, L * u13, Ly * 14】 F «OT (1-14) ratamine 0.39 • Λ · ，》 At · 3 · 0-A (V2, Λ »ν13] ρ« 0Τ (1 · Κ) MM 0.024 t: tW-M € ^ h * 1 · AU ", D-Are1Z, L * 〇l33F« rn-1〇 藤 膝 0.0018 CH #! ^ · 1, AU11 · D'Arfl12, Ι · * υ13ϊρ «Τ &lt; 1 · Ηϊ Fuji base 0 · 0Z6. '〇Κϊ) ί + Μϊ ·' DU12, Lw13】 F # WT〇-m Tengamine '0 * 017' .i [«• 3M.MV * 1, D- * rs12, L * u13, LyiWpMTd ··! *) Proamine Q.1S Al · 11, 0- * re12 · L * u'3, Ly * 14Jp «Ti1-U) brewed m W-HeWw1 · Al · 3 · AU11 · D-Arfl12, Uu13fLy * Ulp #« TU-t〇 amine 0.001 / JU · 3 · Μ · 11, 〇.ΑΓβ12, L * yt3, Ly * ulpiCT (lU) amine 0.001 〇 ** 2 * ^ \ Al · 11, O-Afl12, Uu13, 1 · ν »141ρ« Τ 〔1, 1〇 Saturated amine 0 «003 A ·? · Lw13rLy * t4】 F« mi * U) Triamine 0.003 Dt ^ Ph · 1 · M · 11 · e_AiV2 · Leu13 · D * Ly * Ulf «UVU &gt; Ratamine 〇 · 3? OMWh # 1 · 0 · ΑΓί12, L * u13 · D, CUiUlpWT (1-U &gt; dentamine 〇 · 〇〇〇 * — 4 9 — This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ( Please read the notes on the reverse side and fill in this page) 4342§1 A7 B7 V. Description of the invention (^) Enter compound _ΕΡ; 〇 · Al · 11, O-Arf l12, l * u15t O-Ctn ^ F ^ OTiVU) vine 〇. «Ο-Am12, 0.40 Οί-H ^ ti * 1, Al · 3 * Ali11, 0-ΑΓ912, l * u13,0-Lyi1A1p # WT (1-H) 0.024 M »3 · AU11, O-Ara12, Ltu13, D-Lr», 4lF «0T (1-U) Primary amine: 0,007 W« 2 * iPh · 1 · D-Arg1Z, Leu13, Ly * 14] p # «T (VU) glutamine 0.002 Table 3 (Previous page) Effect of motilin receptor antagonists on intestinal tract of dogs β ED50〇

Mill therefore enumerates some specific examples. It is obvious that the basic structure can be changed to provide other specific examples using the present invention without departing from the spirit and scope of the present invention. All such amendments and changes are included in the scope of the present invention like the scope of the attached patent application, and are not limited to the specific embodiments shown by the examples. '(Please read the notes on the back and fill in this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -50- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

434 mil 55907 Patent Application Check Chinese Patent Application Amendment (October 89) A8 B8 C8 D8 Patent Application Scope A gastrointestinal motility-activating polypeptide • It is represented by the following formula (R,) .i- ^ QHCO-ABDE-Thr-FGH-Leu-IJ-NH ^ (SiRs. ¢ 1): vl -i I I il:? 3 ': 4pK2R4 National Release i2Rsf VIII..4 · Τ Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives including salt formation, B in group A is D and ε is group G in F Η is I, J is optically active isomer type and its pharmaceutically acceptable acid plus which is selected from the group consisting of L-valine, L-isoleucine, and L-leucine Amino acid or L-alanine; selected from the group consisting of L-isoleucine and leucine; L-benzyl alanine; selected from L-tyrosine, L-phenylalanine and L- sister. Glycine or D-alanine; L-glutamine or L-glutamine; L-glutamine, L-glutamine or L-alanine; I and · NΗ -The direct bonding or linking between groups is selected from Z, Z-Leu, Z-Leu-Gln »Z-Leu-Gln-Glu, Z-Leu-GIn-Glu-Lys, Z-Leu-Gln-Glu-Lys -Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg, Z ~ Leu * Gln-Glu-Lys-Glu-Arg-Asn, Z -Leu &quot; Gln_Glu-Lys-Glu-Arg-Asn-Lys, and This paper uses China隼 (CNS) A4 specification (210X297 mm) t read the notes on the back and then fill out this page) 4 $ 42§i A8 B8 C8 D8 VI. Patent application violation Z-L eu-G 1 η-G 1 u-L ys-G 1 u-A r · g-A s η-L ys-G 1 y, where Z is selected from the group consisting of D-arginine, D-isospermine, D-lysine, D-Ornithine, D-2,4-diaminobutyric acid, D-glutamine, D-asparagine, and D-alanine; lower alkyl or propenyl; R2 series Selected from hydrogen, lower alkyl, propargyl, and propenyl; Brother 3 is selected from hydrogen, lower alkyl, and propenyl; 1-4 is selected from cycloalkyl and unsubstituted and aryl, The aryl group may be substituted by one or more substituents selected from the group consisting of hydrogen, hydroxyl, and a lower alkoxy group; RB is selected from an amino alkyl group containing 1 to 3 carbon atoms and 2 or 3 Guanidino alkyl groups of one carbon atom * or when J is Z-Leu or Z-L eu-G 1 η-G 1 u-L ys-G 1 u-A rg-A s η-L ys-G 1 y ., It is CHzCONH2; Re is -C00H or -COHIU, and the * symbol represents an asymmetric carbon that can be in the D or L configuration and each lower alkyl group contains Of 1 to 4 carbon atoms. Printed by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative (please read the cautions on the reverse side, and then fill out this page) 2. According to the peptide of the scope of patent application, the (RiHDUdNeClHCfUIUKO- is selected from L-phenylalanine , D-phenylalanine, L-cyclohexylalanine and D-cyclohexylalanine. 3. Polypeptide according to item 1 of the scope of patent application * where J is a direct coupling or selection between the I and -NH-groups 1 Z-Leu, Z-Leu-GU-Glu, Z-Leu ~ Gln-Glu ~ Lys-Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn, which conforms to the Chinese national standard ( CNS) A4 specification (210X297 mm) ^ A8 B8 CS D8 VI. Application scope Z-Leu-Gln-GIu-Lys-GIu-Arg-Asn-Lys-Gly, and Z is pseudo-selected from D-arginine and D-glutamine. 4. The polypeptide according to item 1 of the scope of patent application, wherein h is selected from cyclohexyl, phenyl, p-fluorophenyl, p-chlorobenzyl, p-bromophenyl, p- -Iodophenyl, p-hydroxyphenyl, p-methoxyphenyl, 1-naphthyl, and 2-zeenyl. 5. The polypeptide according to item 1 of the scope of patent application, wherein the -HHWCH (CH2R5)-Rs The base is selected from D-arginine, lysine, D-ion Acid, glutamic acid, D-glutamic acid, D-guanine acid, D-2,4-diaminobutyric acid and D-spermine acid. (Please read the notes on the back before filling this page) Employees of the Central Procurement Bureau of the Ministry of Economic Affairs shall exempt the cooperatives from printing this paper to the size of the Chinese National Standard (CNS) A4 (210X2? 7 mm). The application date is 83.06.29 Case No. 83105907 The sheds above the category shall be filled in by this bureau) 434261 U Patent Specification 5-Strategic Invention of Employees' Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China ^ I. Plum STIMULATING ACTIVITY &quot; Surname_First name 1. Marc Massireg 2. Ramalin G. de Harani Praga 逹 3. Slims Florence 4. Mary Sue Marvin 5. Orvons Carders Nationality 1.3.4. United States 2. India 3. Maltese invention, I. Domicile and residence 1. American girl No. 8 St. Nica Road, Blanchardburg, Jersey 2. United States 25 Hickory District, Chassen, New Jersey 3. 100 Sida Lake District, Danville, New Jersey, United States 4. 86 Washington Street, Morristown, Jersey 5. American Girl Jersey No. 177, Circle, New Providence,... V Name (Name) • i Omega Pharmaceuticals' _, .1 Nationality US //: 3. Applicant's Residence, Residence (Office) Button, USA Name of Representative No. 110 Free Allan Road, Xizhou CNS) A4 size (210X297 mm) 434 mil 55907 Patent Application Check Chinese Patent Application Amendment (October 89) A8 B8 C8 D8 Patent Application Scope A gastrointestinal motility-activating polypeptide • It is represented by the following formula (R,) .i- ^ QHCO-ABDE-Thr-FGH-Leu-IJ-NH ^ (SiRs. ¢ 1): vl -i I I il:? 3 ': 4pK2R4 National Release i2Rsf VIII..4 · Τ Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives including salt formation, B in group A is D and ε is group G in F Η is I, J is optically active isomer type and its pharmaceutically acceptable acid plus which is selected from the group consisting of L-valine, L-isoleucine, and L-leucine Amino acid or L-alanine; selected from the group consisting of L-isoleucine and leucine; L-benzyl alanine; selected from L-tyrosine, L-phenylalanine and L- sister. Glycine or D-alanine; L-glutamine or L-glutamine; L-glutamine, L-glutamine or L-alanine; I and · NΗ -The direct bonding or linking between groups is selected from Z, Z-Leu, Z-Leu-Gln »Z-Leu-Gln-Glu, Z-Leu-GIn-Glu-Lys, Z-Leu-Gln-Glu-Lys -Glu, Z-Leu-Gln-Glu-Lys-Glu-Arg, Z ~ Leu * Gln-Glu-Lys-Glu-Arg-Asn, Z -Leu &quot; Gln_Glu-Lys-Glu-Arg-Asn-Lys, and This paper uses China Falcon (CNS) A4 size (210X297 mm) t read first heard read the back of the Notes then fill out this page)